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Leptin-Signaling Pathways as Therapeutic Targets in Cancer

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Adipocytokines, Energy Balance, and Cancer

Part of the book series: Energy Balance and Cancer ((EBAC,volume 12))

Abstract

Evidences from molecular, clinical, and epidemiological studies have shown that high plasma level of leptin correlate with obese state and is emerging as a key adipocytokine mediating the molecular effects of obesity on cancer. Dysregulation of leptin influences various stages of carcinogenesis from initiation and growth to metastatic progression. In addition to activating its canonical signaling, leptin is now known to functionally interact with multiple oncogenic pathways. This “hyperactive leptin-signaling network” in cancer cells leads to simultaneous activation of multiple oncogenic pathways leading to increased proliferation, decreased apoptosis, acquisition of mesenchymal phenotype, and enhanced migration and invasion potential of tumor cells. Leptin is also known to interact with other important molecular effectors such as estrogen, IGF-1, insulin, VEGF, and inflammatory cytokines and achieve a wider impact across various tumor types. Development of a better understanding of leptin-signaling network has provided multiple therapeutic opportunities to inhibit important nodes of this network. This article presents an overview of the studies investigating the involvement of leptin and hyperactive leptin-signaling network in cancer progression and strategies to inhibit leptin signaling in cancer.

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References

  1. Rose DP, Komninou D, Stephenson GD (2004) Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev 5:153–165

    Article  CAS  PubMed  Google Scholar 

  2. Ray A, Cleary MP (2012) Obesity and breast cancer: a clinical biochemistry perspective. Clin Biochem 45:189–197

    Article  CAS  PubMed  Google Scholar 

  3. Hursting SD, Berger NA (2010) Energy balance, host-related factors, and cancer progression. J Clin Oncol 28:4058–4065

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    Article  CAS  PubMed  Google Scholar 

  5. Wolk R, Berger P, Lennon RJ, Brilakis ES, Johnson BD, Somers VK (2004) Plasma leptin and prognosis in patients with established coronary atherosclerosis. J Am Coll Cardiol 44:1819–1824

    Article  CAS  PubMed  Google Scholar 

  6. Somasundar P, McFadden DW, Hileman SM, Vona-Davis L (2004) Leptin is a growth factor in cancer. J Surg Res 116:337–349

    Article  CAS  PubMed  Google Scholar 

  7. Singhal A, Farooqi IS, Cole TJ, O’Rahilly S, Fewtrell M, Kattenhorn M, Lucas A, Deanfield J (2002) Influence of leptin on arterial distensibility: a novel link between obesity and cardiovascular disease? Circulation 106:1919–1924

    Article  CAS  PubMed  Google Scholar 

  8. Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P (1996) Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett 387:113–116

    Article  CAS  PubMed  Google Scholar 

  9. Chinookoswong N, Wang JL, Shi ZQ (1999) Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes 48:1487–1492

    Article  CAS  PubMed  Google Scholar 

  10. Pallett AL, Morton NM, Cawthorne MA, Emilsson V (1997) Leptin inhibits insulin secretion and reduces insulin mRNA levels in rat isolated pancreatic islets. Biochem Biophys Res Commun 238:267–270

    Article  CAS  PubMed  Google Scholar 

  11. Maccio A, Madeddu C, Gramignano G, Mulas C, Floris C, Massa D, Astara G, Chessa P, Mantovani G (2010) Correlation of body mass index and leptin with tumor size and stage of disease in hormone-dependent postmenopausal breast cancer: preliminary results and therapeutic implications. J Mol Med (Berl) 88:677–686

    Article  CAS  Google Scholar 

  12. Ishikawa M, Kitayama J, Nagawa H (2004) Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 10:4325–4331

    Article  CAS  PubMed  Google Scholar 

  13. Tessitore L, Vizio B, Jenkins O, De Stefano I, Ritossa C, Argiles JM, Benedetto C, Mussa A (2000) Leptin expression in colorectal and breast cancer patients. Int J Mol Med 5:421–426

    CAS  PubMed  Google Scholar 

  14. Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koda L, Golaszewska J, Russo A, Sulkowski S, Surmacz E (2006) Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli. Clin Cancer Res 12:1447–1453

    Article  CAS  PubMed  Google Scholar 

  15. Wu MH, Chou YC, Chou WY, Hsu GC, Chu CH, Yu CP, Yu JC, Sun CA (2009) Circulating levels of leptin, adiposity and breast cancer risk. Br J Cancer 100:578–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Romero-Figueroa Mdel S, Garduno-Garcia Jde J, Duarte-Mote J, Matute-Gonzalez G, Gomez-Villanueva A, De la Cruz-Vargas J (2013) Insulin and leptin levels in obese patients with and without breast cancer. Clin Breast Cancer 13:482–485

    Article  PubMed  CAS  Google Scholar 

  17. Niu J, Jiang L, Guo W, Shao L, Liu Y, Wang L (2013) The association between leptin level and breast cancer: a meta-analysis. PLoS One 8, e67349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Alshaker H, Sacco K, Alfraidi A, Muhammad A, Winkler M, Pchejetski D (2015) Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma. Oncotarget 6(34):35556–35563

    PubMed  PubMed Central  Google Scholar 

  19. Wright ME, Chang SC, Schatzkin A, Albanes D, Kipnis V, Mouw T, Hurwitz P, Hollenbeck A, Leitzmann MF (2007) Prospective study of adiposity and weight change in relation to prostate cancer incidence and mortality. Cancer 109:675–684

    Article  PubMed  Google Scholar 

  20. Rodriguez C, Freedland SJ, Deka A, Jacobs EJ, McCullough ML, Patel AV, Thun MJ, Calle EE (2007) Body mass index, weight change, and risk of prostate cancer in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 16:63–69

    Article  PubMed  Google Scholar 

  21. Lin DW, FitzGerald LM, Fu R, Kwon EM, Zheng SL, Kolb S, Wiklund F, Stattin P, Isaacs WB, Xu J, Ostrander EA, Feng Z, Gronberg H, Stanford JL (2011) Genetic variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes are prognostic markers of prostate cancer-specific mortality. Cancer Epidemiol Biomarkers Prev 20:1928–1936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chang S, Hursting SD, Contois JH, Strom SS, Yamamura Y, Babaian RJ, Troncoso P, Scardino PS, Wheeler TM, Amos CI, Spitz MR (2001) Leptin and prostate cancer. Prostate 46:62–67

    Article  CAS  PubMed  Google Scholar 

  23. Stattin P, Lukanova A, Biessy C, Soderberg S, Palmqvist R, Kaaks R, Olsson T, Jellum E (2004) Obesity and colon cancer: does leptin provide a link? Int J Cancer 109:149–152

    Article  CAS  PubMed  Google Scholar 

  24. Stattin P, Palmqvist R, Soderberg S, Biessy C, Ardnor B, Hallmans G, Kaaks R, Olsson T (2003) Plasma leptin and colorectal cancer risk: a prospective study in Northern Sweden. Oncol Rep 10:2015–2021

    PubMed  Google Scholar 

  25. Tamakoshi K, Toyoshima H, Wakai K, Kojima M, Suzuki K, Watanabe Y, Hayakawa N, Yatsuya H, Kondo T, Tokudome S, Hashimoto S, Suzuki S, Kawado M, Ozasa K, Ito Y, Tamakoshi A (2005) Leptin is associated with an increased female colorectal cancer risk: a nested case-control study in Japan. Oncology 68:454–461

    Article  CAS  PubMed  Google Scholar 

  26. Guadagni F, Roselli M, Martini F, Spila A, Riondino S, D’Alessandro R, Del Monte G, Formica V, Laudisi A, Portarena I, Palmirotta R, Ferroni P (2009) Prognostic significance of serum adipokine levels in colorectal cancer patients. Anticancer Res 29:3321–3327

    CAS  PubMed  Google Scholar 

  27. Fan YL, Li XQ (2015) Expression of leptin and its receptor in thyroid carcinoma: distinctive prognostic significance in different subtypes. Clin Endocrinol (Oxf) 83:261–267

    Article  CAS  Google Scholar 

  28. Akinci M, Kosova F, Cetin B, Aslan S, Ari Z, Cetin A (2009) Leptin levels in thyroid cancer. Asian J Surg 32:216–223

    Article  PubMed  Google Scholar 

  29. Wang PP, He XY, Wang R, Wang Z, Wang YG (2014) High leptin level is an independent risk factor of endometrial cancer: a meta-analysis. Cell Physiol Biochem 34:1477–1484

    Article  CAS  PubMed  Google Scholar 

  30. Zhang Y, Liu L, Li C, Ai H (2014) Correlation analysis between the expressions of leptin and its receptor (ObR) and clinicopathology in endometrial cancer. Cancer Biomark 14:353–359

    CAS  PubMed  Google Scholar 

  31. Knight BB, Oprea-Ilies GM, Nagalingam A, Yang L, Cohen C, Saxena NK, Sharma D (2011) Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells. Endocr Relat Cancer 18:413–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lee WM, Lu S, Medline A, Archer MC (2001) Susceptibility of lean and obese Zucker rats to tumorigenesis induced by N-methyl-N-nitrosourea. Cancer Lett 162:155–160

    Article  CAS  PubMed  Google Scholar 

  33. Saxena NK, Vertino PM, Anania FA, Sharma D (2007) leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3. J Biol Chem 282:13316–13325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Saxena NK, Sharma D (2013) Multifaceted leptin network: the molecular connection between obesity and breast cancer. J Mammary Gland Biol Neoplasia 18:309–320

    Article  PubMed  PubMed Central  Google Scholar 

  35. Taliaferro-Smith L, Nagalingam A, Knight BB, Oberlick E, Saxena NK, Sharma D (2013) Integral role of PTP1B in adiponectin-mediated inhibition of oncogenic actions of leptin in breast carcinogenesis. Neoplasia 15:23–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Byrne AM, Bouchier-Hayes DJ, Harmey JH (2005) Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med 9:777–794

    Article  CAS  PubMed  Google Scholar 

  37. Miyazawa-Hoshimoto S, Takahashi K, Bujo H, Hashimoto N, Saito Y (2003) Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obese subjects. Diabetologia 46:1483–1488

    Article  CAS  PubMed  Google Scholar 

  38. Liu Y, Tamimi RM, Collins LC, Schnitt SJ, Gilmore HL, Connolly JL, Colditz GA (2011) The association between vascular endothelial growth factor expression in invasive breast cancer and survival varies with intrinsic subtypes and use of adjuvant systemic therapy: results from the Nurses’ Health Study. Breast Cancer Res Treat 129:175–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Makey KL, Patterson SG, Robinson J, Loftin M, Waddell DE, Miele L, Chinchar E, Huang M, Smith AD, Weber M, Gu JW (2013) Increased plasma levels of soluble vascular endothelial growth factor receptor 1 (sFlt-1) in women by moderate exercise and increased plasma levels of vascular endothelial growth factor in overweight/obese women. Eur J Cancer Prev 22:83–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Saxena NK, Taliaferro-Smith L, Knight BB, Merlin D, Anania FA, O’Regan RM, Sharma D (2008) Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor. Cancer Res 68:9712–9722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yan D, Avtanski D, Saxena NK, Sharma D (2012) Leptin-induced epithelial-mesenchymal transition in breast cancer cells requires beta-catenin activation via Akt/GSK3- and MTA1/Wnt1 protein-dependent pathways. J Biol Chem 287:8598–8612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Khanal T, Kim HG, Do MT, Choi JH, Won SS, Kang W, Chung YC, Jeong TC, Jeong HG (2014) Leptin induces CYP1B1 expression in MCF-7 cells through ligand-independent activation of the ERalpha pathway. Toxicol Appl Pharmacol 277:39–48

    Article  CAS  PubMed  Google Scholar 

  43. Catalano S, Mauro L, Marsico S, Giordano C, Rizza P, Rago V, Montanaro D, Maggiolini M, Panno ML, Ando S (2004) Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. J Biol Chem 279:19908–19915

    Article  CAS  PubMed  Google Scholar 

  44. Catalano S, Marsico S, Giordano C, Mauro L, Rizza P, Panno ML, Ando S (2003) Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J Biol Chem 278:28668–28676

    Article  CAS  PubMed  Google Scholar 

  45. Noda T, Kikugawa T, Tanji N, Miura N, Asai S, Higashiyama S, Yokoyama M (2015) Longterm exposure to leptin enhances the growth of prostate cancer cells. Int J Oncol 46:1535–1542

    PubMed  Google Scholar 

  46. Hoda MR, Theil G, Mohammed N, Fischer K, Fornara P (2012) The adipocyte-derived hormone leptin has proliferative actions on androgen-resistant prostate cancer cells linking obesity to advanced stages of prostate cancer. J Oncol 2012:280386

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Onuma M, Bub JD, Rummel TL, Iwamoto Y (2003) Prostate cancer cell-adipocyte interaction: leptin mediates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase. J Biol Chem 278:42660–42667

    Article  CAS  PubMed  Google Scholar 

  48. Samuel-Mendelsohn S, Inbar M, Weiss-Messer E, Niv-Spector L, Gertler A, Barkey RJ (2011) Leptin signaling and apoptotic effects in human prostate cancer cell lines. Prostate 71:929–945

    Article  CAS  PubMed  Google Scholar 

  49. Frankenberry KA, Somasundar P, McFadden DW, Vona-Davis LC (2004) Leptin induces cell migration and the expression of growth factors in human prostate cancer cells. Am J Surg 188:560–565

    Article  CAS  PubMed  Google Scholar 

  50. Somasundar P, Frankenberry KA, Skinner H, Vedula G, McFadden DW, Riggs D, Jackson B, Vangilder R, Hileman SM, Vona-Davis LC (2004) Prostate cancer cell proliferation is influenced by leptin. J Surg Res 118:71–82

    Article  CAS  PubMed  Google Scholar 

  51. Deo DD, Rao AP, Bose SS, Ouhtit A, Baliga SB, Rao SA, Trock BJ, Thouta R, Raj MH, Rao PN (2008) Differential effects of leptin on the invasive potential of androgen-dependent and -independent prostate carcinoma cells. J Biomed Biotechnol 2008:163902

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Huang CY, Yu HS, Lai TY, Yeh YL, Su CC, Hsu HH, Tsai FJ, Tsai CH, Wu HC, Tang CH (2011) Leptin increases motility and integrin up-regulation in human prostate cancer cells. J Cell Physiol 226:1274–1282

    Article  CAS  PubMed  Google Scholar 

  53. Ngo TH, Barnard RJ, Cohen P, Freedland S, Tran C, deGregorio F, Elshimali YI, Heber D, Aronson WJ (2003) Effect of isocaloric low-fat diet on human LAPC-4 prostate cancer xenografts in severe combined immunodeficient mice and the insulin-like growth factor axis. Clin Cancer Res 9:2734–2743

    CAS  PubMed  Google Scholar 

  54. Nakajima TE, Yamada Y, Hamano T, Furuta K, Matsuda T, Fujita S, Kato K, Hamaguchi T, Shimada Y (2010) Adipocytokines as new promising markers of colorectal tumors: adiponectin for colorectal adenoma, and resistin and visfatin for colorectal cancer. Cancer Sci 101:1286–1291

    Article  CAS  PubMed  Google Scholar 

  55. Aparicio T, Kotelevets L, Tsocas A, Laigneau JP, Sobhani I, Chastre E, Lehy T (2005) Leptin stimulates the proliferation of human colon cancer cells in vitro but does not promote the growth of colon cancer xenografts in nude mice or intestinal tumorigenesis in Apc(Min/+) mice. Gut 54:1136–1145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hardwick JC, Van Den Brink GR, Offerhaus GJ, Van Deventer SJ, Peppelenbosch MP (2001) Leptin is a growth factor for colonic epithelial cells. Gastroenterology 121:79–90

    Article  CAS  PubMed  Google Scholar 

  57. Pai R, Lin C, Tran T, Tarnawski A (2005) Leptin activates STAT and ERK2 pathways and induces gastric cancer cell proliferation. Biochem Biophys Res Commun 331:984–992

    Article  CAS  PubMed  Google Scholar 

  58. Sobhani I, Bado A, Vissuzaine C, Buyse M, Kermorgant S, Laigneau JP, Attoub S, Lehy T, Henin D, Mignon M, Lewin MJ (2000) Leptin secretion and leptin receptor in the human stomach. Gut 47:178–183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Attoub S, Noe V, Pirola L, Bruyneel E, Chastre E, Mareel M, Wymann MP, Gespach C (2000) Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3-kinase-, rho-, and rac-dependent signaling pathways. FASEB J 14:2329–2338

    Article  CAS  PubMed  Google Scholar 

  60. Somasundar P, Riggs D, Jackson B, Vona-Davis L, McFadden DW (2003) Leptin stimulates esophageal adenocarcinoma growth by nonapoptotic mechanisms. Am J Surg 186:575–578

    Article  CAS  PubMed  Google Scholar 

  61. Amemori S, Ootani A, Aoki S, Fujise T, Shimoda R, Kakimoto T, Shiraishi R, Sakata Y, Tsunada S, Iwakiri R, Fujimoto K (2007) Adipocytes and preadipocytes promote the proleration of colon cancer cells in vitro. Am J Physiol Gastrointest Liver Physiol 292:G923–G929

    Google Scholar 

  62. Wang W, Yan H, Dou C, Su Y (2013) Human leptin triggers proliferation of A549 cells via blocking endoplasmic reticulum stress-related apoptosis. Biochemistry (Mosc) 78:1333–1341

    Article  CAS  Google Scholar 

  63. Lai Q, Sun Y (2013) Human leptin protein induces proliferation of A549 cells via inhibition of PKR-like ER kinase and activating transcription factor-6 mediated apoptosis. Yonsei Med J 54:1407–1415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Feng H, Liu Q, Zhang N, Zheng L, Sang M, Feng J, Zhang J, Wu X, Shan B (2013) Leptin promotes metastasis by inducing an epithelial-mesenchymal transition in A549 lung cancer cells. Oncol Res 21:165–171

    Article  PubMed  CAS  Google Scholar 

  65. Petridou E, Belechri M, Dessypris N, Koukoulomatis P, Diakomanolis E, Spanos E, Trichopoulos D (2002) Leptin and body mass index in relation to endometrial cancer risk. Ann Nutr Metab 46:147–151

    Article  CAS  PubMed  Google Scholar 

  66. Yuan SS, Tsai KB, Chung YF, Chan TF, Yeh YT, Tsai LY, Su JH (2004) Aberrant expression and possible involvement of the leptin receptor in endometrial cancer. Gynecol Oncol 92:769–775

    Article  CAS  PubMed  Google Scholar 

  67. Sharma D, Saxena NK, Vertino PM, Anania FA (2006) Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways. Endocr Relat Cancer 13:629–640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Koda M, Sulkowska M, Wincewicz A, Kanczuga-Koda L, Musiatowicz B, Szymanska M, Sulkowski S (2007) Expression of leptin, leptin receptor, and hypoxia-inducible factor 1 alpha in human endometrial cancer. Ann N Y Acad Sci 1095:90–98

    Article  CAS  PubMed  Google Scholar 

  69. Catalano S, Giordano C, Rizza P, Gu G, Barone I, Bonofiglio D, Giordano F, Malivindi R, Gaccione D, Lanzino M, De Amicis F, Ando S (2009) Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation. J Cell Physiol 218:490–500

    Article  CAS  PubMed  Google Scholar 

  70. Carino C, Olawaiye AB, Cherfils S, Serikawa T, Lynch MP, Rueda BR, Gonzalez RR (2008) Leptin regulation of proangiogenic molecules in benign and cancerous endometrial cells. Int J Cancer 123:2782–2790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Stolzenberg-Solomon RZ, Newton CC, Silverman DT, Pollak M, Nogueira LM, Weinstein SJ, Albanes D, Mannisto S, Jacobs EJ (2015) Circulating leptin and risk of pancreatic cancer: a pooled analysis from 3 cohorts. Am J Epidemiol 182:187–197

    Article  PubMed  PubMed Central  Google Scholar 

  72. Mendonsa AM, Chalfant MC, Gorden LD, VanSaun MN (2015) Modulation of the leptin receptor mediates tumor growth and migration of pancreatic cancer cells. PLoS One 10, e0126686

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Fan Y, Gan Y, Shen Y, Cai X, Song Y, Zhao F, Yao M, Gu J, Tu H (2015) Leptin signaling enhances cell invasion and promotes the metastasis of human pancreatic cancer via increasing MMP-13 production. Oncotarget 6:16120–16134

    Article  PubMed  PubMed Central  Google Scholar 

  74. Ren H, Jia L, Zhao T, Zhang H, Chen J, Yang S, Liu J, Yu M, Hao J (2014) Hypoxia inducible factor (HIF)-1alpha directly activates leptin receptor (Ob-R) in pancreatic cancer cells. Cancer Lett 354:172–180

    Article  CAS  PubMed  Google Scholar 

  75. Tartaglia LA (1997) The leptin receptor. J Biol Chem 272:6093–6096

    Article  CAS  PubMed  Google Scholar 

  76. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271

    Article  CAS  PubMed  Google Scholar 

  77. Ahima RS, Osei SY (2004) Leptin signaling. Physiol Behav 81:223–241

    Article  CAS  PubMed  Google Scholar 

  78. Jiang L, You J, Yu X, Gonzalez L, Yu Y, Wang Q, Yang G, Li W, Li C, Liu Y (2008) Tyrosine-dependent and -independent actions of leptin receptor in control of energy balance and glucose homeostasis. Proc Natl Acad Sci U S A 105:18619–18624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gao Q, Wolfgang MJ, Neschen S, Morino K, Horvath TL, Shulman GI, Fu XY (2004) Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc Natl Acad Sci U S A 101:4661–4666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Piper ML, Unger EK, Myers MG Jr, Xu AW (2008) Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons. Mol Endocrinol 22:751–759

    Article  CAS  PubMed  Google Scholar 

  81. Zhang EE, Chapeau E, Hagihara K, Feng GS (2004) Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc Natl Acad Sci U S A 101:16064–16069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bjorbaek C, El-Haschimi K, Frantz JD, Flier JS (1999) The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem 274:30059–30065

    Article  CAS  PubMed  Google Scholar 

  83. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, Kim YB, Elmquist JK, Tartaglia LA, Kahn BB, Neel BG (2002) PTP1B regulates leptin signal transduction in vivo. Dev Cell 2:489–495

    Article  CAS  PubMed  Google Scholar 

  84. Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, Anania FA (2007) Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res 67:2497–2507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gonzalez RR, Leavis P (2001) Leptin upregulates beta3-integrin expression and interleukin-1beta, upregulates leptin and leptin receptor expression in human endometrial epithelial cell cultures. Endocrine 16:21–28

    Article  CAS  PubMed  Google Scholar 

  86. Pinteaux E, Inoue W, Schmidt L, Molina-Holgado F, Rothwell NJ, Luheshi GN (2007) Leptin induces interleukin-1beta release from rat microglial cells through a caspase 1 independent mechanism. J Neurochem 102:826–833

    Article  CAS  PubMed  Google Scholar 

  87. Gonzalez RR, Devoto L, Campana A, Bischof P (2001) Effects of leptin, interleukin-1alpha, interleukin-6, and transforming growth factor-beta on markers of trophoblast invasive phenotype: integrins and metalloproteinases. Endocrine 15:157–164

    Article  CAS  PubMed  Google Scholar 

  88. Gonzalez RR, Cherfils S, Escobar M, Yoo JH, Carino C, Styer AK, Sullivan BT, Sakamoto H, Olawaiye A, Serikawa T, Lynch MP, Rueda BR (2006) Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2). J Biol Chem 281:26320–26328

    Article  CAS  PubMed  Google Scholar 

  89. Perera CN, Chin HG, Duru N, Camarillo IG (2008) Leptin-regulated gene expression in MCF-7 breast cancer cells: mechanistic insights into leptin-regulated mammary tumor growth and progression. J Endocrinol 199:221–233

    Article  CAS  PubMed  Google Scholar 

  90. Housa D, Housova J, Vernerova Z, Haluzik M (2006) Adipocytokines and cancer. Physiol Res 55:233–244

    CAS  PubMed  Google Scholar 

  91. Sharma D, Blum J, Yang X, Beaulieu N, Macleod AR, Davidson NE (2005) Release of methyl CpG binding proteins and histone deacetylase 1 from the Estrogen receptor alpha (ER) promoter upon reactivation in ER-negative human breast cancer cells. Mol Endocrinol 19:1740–1751

    Article  CAS  PubMed  Google Scholar 

  92. Chen C, Chang YC, Liu CL, Chang KJ, Guo IC (2006) Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. Breast Cancer Res Treat 98:121–132

    Article  CAS  PubMed  Google Scholar 

  93. Okumura M, Yamamoto M, Sakuma H, Kojima T, Maruyama T, Jamali M, Cooper DR, Yasuda K (2002) Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-alpha and PPAR expression. Biochim Biophys Acta 1592:107–116

    Article  CAS  PubMed  Google Scholar 

  94. Ray A, Nkhata KJ, Cleary MP (2007) Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status. Int J Oncol 30:1499–1509

    CAS  PubMed  Google Scholar 

  95. Zheng Q, Hursting SD, Reizes O (2012) Leptin regulates cyclin D1 in luminal epithelial cells of mouse MMTV-Wnt-1 mammary tumors. J Cancer Res Clin Oncol 138:1607–1612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jiang H, Yu J, Guo H, Song H, Chen S (2008) Upregulation of survivin by leptin/STAT3 signaling in MCF-7 cells. Biochem Biophys Res Commun 368:1–5

    Article  CAS  PubMed  Google Scholar 

  97. Palianopoulou M, Papanikolaou V, Stefanou N, Tsezou A (2011) The activation of leptin-mediated survivin is limited by the inducible suppressor SOCS-3 in MCF-7 cells. Exp Biol Med (Maywood) 236:70–76

    Article  CAS  Google Scholar 

  98. Shida D, Kitayama J, Mori K, Watanabe T, Nagawa H (2005) Transactivation of epidermal growth factor receptor is involved in leptin-induced activation of janus-activated kinase 2 and extracellular signal-regulated kinase 1/2 in human gastric cancer cells. Cancer Res 65:9159–9163

    Article  CAS  PubMed  Google Scholar 

  99. Ogunwobi OO, Beales IL (2008) Leptin stimulates the proliferation of human oesophageal adenocarcinoma cells via HB-EGF and Tgfalpha mediated transactivation of the epidermal growth factor receptor. Br J Biomed Sci 65:121–127

    Article  CAS  PubMed  Google Scholar 

  100. Guo S, Gonzalez-Perez RR (2011) Notch, IL-1 and leptin crosstalk outcome (NILCO) is critical for leptin-induced proliferation, migration and VEGF/VEGFR-2 expression in breast cancer. PLoS One 6, e21467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Fusco R, Galgani M, Procaccini C, Franco R, Pirozzi G, Fucci L, Laccetti P, Matarese G (2010) Cellular and molecular crosstalk between leptin receptor and estrogen receptor-{alpha} in breast cancer: molecular basis for a novel therapeutic setting. Endocr Relat Cancer 17:373–382

    Article  CAS  PubMed  Google Scholar 

  102. Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N Engl J Med 354:270–282

    Article  CAS  PubMed  Google Scholar 

  103. Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, Amarneh B, Ito Y, Fisher CR, Michael MD et al (1994) Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev 15:342–355

    CAS  PubMed  Google Scholar 

  104. Yu W, Gu JC, Liu JZ, Wang SH, Wang Y, Zhang ZT, Ma XM, Song MM (2010) Regulation of estrogen receptors alpha and beta in human breast carcinoma by exogenous leptin in nude mouse xenograft model. Chin Med J (Engl) 123:337–343

    CAS  Google Scholar 

  105. Valle A, Sastre-Serra J, Oliver J, Roca P (2011) Chronic leptin treatment sensitizes MCF-7 breast cancer cells to estrogen. Cell Physiol Biochem 28:823–832

    Article  CAS  PubMed  Google Scholar 

  106. Binai NA, Damert A, Carra G, Steckelbroeck S, Lower J, Lower R, Wessler S (2010) Expression of estrogen receptor alpha increases leptin-induced STAT3 activity in breast cancer cells. Int J Cancer 127:55–66

    Article  CAS  PubMed  Google Scholar 

  107. Habib CN, Al-Abd AM, Tolba MF, Khalifa AE, Khedr A, Mosli HA, Abdel-Naim AB (2015) Leptin influences estrogen metabolism and accelerates prostate cell proliferation. Life Sci 121:10–15

    Article  CAS  PubMed  Google Scholar 

  108. Bartella V, Cascio S, Fiorio E, Auriemma A, Russo A, Surmacz E (2008) Insulin-dependent leptin expression in breast cancer cells. Cancer Res 68:4919–4927

    Article  CAS  PubMed  Google Scholar 

  109. Jernstrom H, Barrett-Connor E (1999) Obesity, weight change, fasting insulin, proinsulin, C-peptide, and insulin-like growth factor-1 levels in women with and without breast cancer: the Rancho Bernardo Study. J Womens Health Gend Based Med 8:1265–1272

    Article  CAS  PubMed  Google Scholar 

  110. Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE, Li J, Ho GY, Xue X, Anderson GL, Kaplan RC, Harris TG, Howard BV, Wylie-Rosett J, Burk RD, Strickler HD (2009) Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 101:48–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ozbay T, Nahta R (2008) A novel unidirectional cross-talk from the insulin-like growth factor-I receptor to leptin receptor in human breast cancer cells. Mol Cancer Res 6:1052–1058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Fenton JI, Lavigne JA, Perkins SN, Liu H, Chandramouli GV, Shih JH, Hord NG, Hursting SD (2008) Microarray analysis reveals that leptin induces autocrine/paracrine cascades to promote survival and proliferation of colon epithelial cells in an Apc genotype-dependent fashion. Mol Carcinog 47:9–21

    Article  CAS  PubMed  Google Scholar 

  113. Gertler A (2006) Development of leptin antagonists and their potential use in experimental biology and medicine. Trends Endocrinol Metab 17:372–378

    Article  CAS  PubMed  Google Scholar 

  114. Solomon G, Niv-Spector L, Gonen-Berger D, Callebaut I, Djiane J, Gertler A (2006) Preparation of leptin antagonists by site-directed mutagenesis of human, ovine, rat, and mouse leptin’s site III: implications on blocking undesired leptin action in vivo. Ann N Y Acad Sci 1091:531–539

    Article  CAS  PubMed  Google Scholar 

  115. Verploegen SA, Plaetinck G, Devos R, Van der Heyden J, Guisez Y (1997) A human leptin mutant induces weight gain in normal mice. FEBS Lett 405:237–240

    Article  CAS  PubMed  Google Scholar 

  116. Niv-Spector L, Gonen-Berger D, Gourdou I, Biener E, Gussakovsky EE, Benomar Y, Ramanujan KV, Taouis M, Herman B, Callebaut I, Djiane J, Gertler A (2005) Identification of the hydrophobic strand in the A-B loop of leptin as major binding site III: implications for large-scale preparation of potent recombinant human and ovine leptin antagonists. Biochem J 391:221–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gonzalez RR, Leavis PC (2003) A peptide derived from the human leptin molecule is a potent inhibitor of the leptin receptor function in rabbit endometrial cells. Endocrine 21:185–195

    Article  CAS  PubMed  Google Scholar 

  118. Gertler A, Solomon G (2013) Leptin-activity blockers: development and potential use in experimental biology and medicine. Can J Physiol Pharmacol 91:873–882

    Article  CAS  PubMed  Google Scholar 

  119. Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K, Uchida S, Ito Y, Takakuwa K, Matsui J, Takata M, Eto K, Terauchi Y, Komeda K, Tsunoda M, Murakami K, Ohnishi Y, Naitoh T, Yamamura K, Ueyama Y, Froguel P, Kimura S, Nagai R, Kadowaki T (2003) Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem 278:2461–2468

    Article  CAS  PubMed  Google Scholar 

  120. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947–953

    Article  CAS  PubMed  Google Scholar 

  121. Kelesidis I, Kelesidis T, Mantzoros CS (2006) Adiponectin and cancer: a systematic review. Br J Cancer 94:1221–1225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Govindarajan R, Ratnasinghe L, Simmons DL, Siegel ER, Midathada MV, Kim L, Kim PJ, Owens RJ, Lang NP (2007) Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 25:1476–1481

    Article  CAS  PubMed  Google Scholar 

  123. Majuri A, Santaniemi M, Rautio K, Kunnari A, Vartiainen J, Ruokonen A, Kesaniemi YA, Tapanainen JS, Ukkola O, Morin-Papunen L (2007) Rosiglitazone treatment increases plasma levels of adiponectin and decreases levels of resistin in overweight women with PCOS: a randomized placebo-controlled study. Eur J Endocrinol 156:263–269

    Article  CAS  PubMed  Google Scholar 

  124. Osei K, Gaillard T, Kaplow J, Bullock M, Schuster D (2004) Effects of rosglitazone on plasma adiponectin, insulin sensitivity, and insulin secretion in high-risk African Americans with impaired glucose tolerance test and type 2 diabetes. Metabolism 53:1552–1557

    Article  CAS  PubMed  Google Scholar 

  125. Taliaferro-Smith L, Nagalingam A, Zhong D, Zhou W, Saxena NK, Sharma D (2009) LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and inhibition of migration and invasion of breast cancer cells. Oncogene 28:2621–2633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Gonzalez-Angulo AM, Meric-Bernstam F (2010) Metformin: a therapeutic opportunity in breast cancer. Clin Cancer Res 16:1695–1700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Nagalingam A, Arbiser JL, Bonner MY, Saxena NK, Sharma D (2012) Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis. Breast Cancer Res 14:R35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Avtanski DB, Nagalingam A, Bonner MY, Arbiser JL, Saxena NK, Sharma D (2015) Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer. Oncotarget 6:29947–29962

    Article  PubMed  PubMed Central  Google Scholar 

  129. Avtanski DB, Nagalingam A, Kuppusamy P, Bonner MY, Arbiser JL, Saxena NK, Sharma D (2015) Honokiol abrogates leptin-induced tumor progression by inhibiting Wnt1-MTA1-beta-catenin signaling axis in a microRNA-34a dependent manner. Oncotarget 6:16396–16410

    Article  PubMed  PubMed Central  Google Scholar 

  130. Kim SH, Nagalingam A, Saxena NK, Singh SV, Sharma D (2011) Benzyl isothiocyanate inhibits oncogenic actions of leptin in human breast cancer cells by suppressing activation of signal transducer and activator of transcription 3. Carcinogenesis 32:359–367

    Article  PubMed  CAS  Google Scholar 

  131. Zhu Z, Jiang W, Zacher JH, Neil ES, McGinley JN, Thompson HJ (2012) Effects of energy restriction and wheel running on mammary carcinogenesis and host systemic factors in a rat model. Cancer Prev Res (Phila) 5:414–422

    Article  CAS  Google Scholar 

  132. De Lorenzo MS, Baljinnyam E, Vatner DE, Abarzua P, Vatner SF, Rabson AB (2011) Caloric restriction reduces growth of mammary tumors and metastases. Carcinogenesis 32:1381–1387

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Otvos L Jr, Haspinger E, La Russa F, Maspero F, Graziano P, Kovalszky I, Lovas S, Nama K, Hoffmann R, Knappe D, Cassone M, Wade J, Surmacz E (2011) Design and development of a peptide-based adiponectin receptor agonist for cancer treatment. BMC Biotechnol 11:90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Swarbrick MM, Havel PJ (2008) Physiological, pharmacological, and nutritional regulation of circulating adiponectin concentrations in humans. Metab Syndr Relat Disord 6:87–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Dogan S1, Hu X, Zhang Y, Maihle NJ, Grande JP, Cleary MP (2007) Effects of high-fat diet and/or body weight on mammary tumor leptin and apoptosis signaling pathways in MMTV-TGF-alpha mice. Breast Cancer Res 9(6):R91

    Google Scholar 

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Financial Support

This work was supported by NIDDK NIH, K01DK076742 and R03DK089130 (to N.K.S.); NCI NIH R01CA131294, NCI NIH R21CA155686, Avon Foundation, Breast Cancer Research Foundation (BCRF) 90047965 (to D.S.).

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Authors and Affiliations

  1. Department of Medicine, University of Maryland School of Medicine, 660 W Redwood Street, Howard Hall, Room 301, Baltimore, MD, 21201, USA

    Neeraj K. Saxena Ph.D.

  2. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB 1, Room 145, Baltimore, MD, 21231, USA

    Dipali Sharma Ph.D.

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  1. Neeraj K. Saxena Ph.D.
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  2. Dipali Sharma Ph.D.
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Correspondence to Neeraj K. Saxena Ph.D. or Dipali Sharma Ph.D. .

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Editors and Affiliations

  1. Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA

    Ofer Reizes

  2. Center for Science, Health and Society, Case Western Reserve University, Cleveland, Ohio, USA

    Nathan A. Berger

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Saxena, N.K., Sharma, D. (2017). Leptin-Signaling Pathways as Therapeutic Targets in Cancer. In: Reizes, O., Berger, N. (eds) Adipocytokines, Energy Balance, and Cancer. Energy Balance and Cancer, vol 12. Springer, Cham. https://doi.org/10.1007/978-3-319-41677-9_4

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