Skip to main content

Advertisement

SpringerLink
Log in

Targeting autophagy in lymphomas: a double-edged sword?

  • Review Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Autophagy (also known as macroautophagy) is a lysosomal degradation pathway for the clearance of cellular materials, which manifests as an adaptive response to stress stimuli. Over the past decade, numerous studies have linked autophagy with cancer initiation, progression, and chemoresistance. Autophagy defects in normal cells facilitate tumorigenesis; paradoxically, enhanced autophagy allows prolonged survival in cancer cells upon nutrient shortage, low oxygen, or chemotherapies. However, the mechanism underlying the switch from the cytoprotective role of autophagy to autophagic cell death remains incompletely understood. Here, I review the latest advances in understanding the role of autophagy in lymphomas, current challenges, and future directions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. De Duve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J. 1955;60(4):604–17.

    Article  PubMed Central  Google Scholar 

  2. Klionsky DJ. Autophagy revisited: a conversation with Christian de Duve. Autophagy. 2008;4(6):740–3.

    Article  PubMed  Google Scholar 

  3. Novikoff AB, Beaufay H, De Duve C. Electron microscopy of lysosomerich fractions from rat liver. J Biophys Biochem Cytol. 1956;2(4 Suppl):179–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ashford TP, Porter KR. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol. 1962;12:198–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. de Duve C. The lysosome turns fifty. Nat Cell Biol. 2005;7(9):847–9.

    Article  PubMed  CAS  Google Scholar 

  6. De Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435–92.

    Article  PubMed  Google Scholar 

  7. Takeshige K, Baba M, Tsuboi S, Noda T, Ohsumi Y. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol. 1992;119(2):301–11.

    Article  CAS  PubMed  Google Scholar 

  8. Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 1993;333(1–2):169–74.

    Article  CAS  PubMed  Google Scholar 

  9. Titorenko VI, Keizer I, Harder W, Veenhuis M. Isolation and characterization of mutants impaired in the selective degradation of peroxisomes in the yeast Hansenula polymorpha. J Bacteriol. 1995;177(2):357–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yuan W, Tuttle DL, Shi YJ, Ralph GS, Dunn WA Jr. Glucose-induced microautophagy in Pichia pastoris requires the alpha-subunit of phosphofructokinase. J Cell Sci. 1997;110(Pt 16):1935–45.

    CAS  PubMed  Google Scholar 

  11. Yuan W, Stromhaug PE, Dunn WA Jr. Glucose-induced autophagy of peroxisomes in Pichia pastoris requires a unique E1-like protein. Mol Biol Cell. 1999;10(5):1353–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mukaiyama H, Oku M, Baba M, Samizo T, Hammond AT, Glick BS, et al. Paz2 and 13 other PAZ gene products regulate vacuolar engulfment of peroxisomes during micropexophagy. Genes Cells. 2002;7(1):75–90.

    Article  CAS  PubMed  Google Scholar 

  13. Mizushima N. Noboru Mizushima: all about autophagy. Interview by Caitlin Sedwick. J Cell Biol. 2010;190(6):946–7.

    Article  PubMed  Google Scholar 

  14. Mizushima N, Sugita H, Yoshimori T, Ohsumi Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem. 1998;273(51):33889–92.

    Article  CAS  PubMed  Google Scholar 

  15. Mizushima N, Kuma A, Kobayashi Y, Yamamoto A, Matsubae M, Takao T, et al. Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J Cell Sci. 2003;116(Pt 9):1679–88.

    Article  CAS  PubMed  Google Scholar 

  16. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000;19(21):5720–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol. 2001;152(4):657–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432(7020):1032–6.

    Article  CAS  PubMed  Google Scholar 

  19. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2004;15(3):1101–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Melendez A, Levine B. Autophagy in C. elegans. WormBook. 2009;1–26.

  21. Hanaoka H, Noda T, Shirano Y, Kato T, Hayashi H, Shibata D, et al. Leaf senescence and starvation-induced chlorosis are accelerated by the disruption of an Arabidopsis autophagy gene. Plant Physiol. 2002;129(3):1181–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Doelling JH, Walker JM, Friedman EM, Thompson AR, Vierstra RD. The APG8/12-activating enzyme APG7 is required for proper nutrient recycling and senescence in Arabidopsis thaliana. J Biol Chem. 2002;277(36):33105–14.

    Article  CAS  PubMed  Google Scholar 

  23. Lorincz P, Mauvezin C, Juhasz G. Exploring autophagy in Drosophila. Cells. 2017;6(3):22.

    Article  PubMed Central  Google Scholar 

  24. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441(7095):885–9.

    Article  CAS  PubMed  Google Scholar 

  25. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007;131(6):1149–63.

    Article  CAS  PubMed  Google Scholar 

  26. Tsukamoto S, Kuma A, Murakami M, Kishi C, Yamamoto A, Mizushima N. Autophagy is essential for preimplantation development of mouse embryos. Science. 2008;321(5885):117–20.

    Article  CAS  PubMed  Google Scholar 

  27. Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol. 2010;12(9):823–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011;469(7330):323–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jiang P, Mizushima N. Autophagy and human diseases. Cell Res. 2014;24(1):69–79.

    Article  CAS  PubMed  Google Scholar 

  30. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728–41.

    Article  CAS  PubMed  Google Scholar 

  31. Harris J. Autophagy and cytokines. Cytokine. 2011;56(2):140–4.

    Article  CAS  PubMed  Google Scholar 

  32. Kongara S, Karantza V. The interplay between autophagy and ROS in tumorigenesis. Front Oncol. 2012;2:171.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Li L, Ishdorj G, Gibson SB. Reactive oxygen species regulation of autophagy in cancer: implications for cancer treatment. Free Radic Biol Med. 2012;53(7):1399–410.

    Article  CAS  PubMed  Google Scholar 

  34. Chen Z, Teo AE, McCarty N. ROS-induced CXCR4 signaling regulates mantle cell lymphoma (MCL) cell survival and drug resistance in the bone marrow microenvironment via autophagy. Clin Cancer Res. 2016;22(1):187–99.

    Article  CAS  PubMed  Google Scholar 

  35. Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013;4:e838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang H, Chen Z, Miranda RN, Medeiros LJ, McCarty N. TG2 and NF-kappaB signaling coordinates the survival of mantle cell lymphoma cells via IL6-mediated autophagy. Cancer Res. 2016;76(21):6410–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang H, McCarty N. Tampering with cancer chemoresistance by targeting the TGM2-IL6-autophagy regulatory network. Autophagy. 2017;13(3):627–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Colombo MI. Autophagy: a pathogen driven process. IUBMB Life. 2007;59(4–5):238–42.

    Article  CAS  PubMed  Google Scholar 

  39. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402(6762):672–6.

    Article  CAS  PubMed  Google Scholar 

  40. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112(12):1809–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA. 2003;100(25):15077–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen Y, Lu Y, Lu C, Zhang L. Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-1alpha expression. Pathol Oncol Res. 2009;15(3):487–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ding ZB, Shi YH, Zhou J, Qiu SJ, Xu Y, Dai Z, et al. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res. 2008;68(22):9167–75.

    Article  CAS  PubMed  Google Scholar 

  44. Pirtoli L, Cevenini G, Tini P, Vannini M, Oliveri G, Marsili S, et al. The prognostic role of Beclin 1 protein expression in high-grade gliomas. Autophagy. 2009;5(7):930–6.

    Article  PubMed  Google Scholar 

  45. Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 2011;25(8):795–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science. 2011;334(6062):1573–7.

    Article  CAS  PubMed  Google Scholar 

  47. Janku F, McConkey DJ, Hong DS, Kurzrock R. Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol. 2011;8(9):528–39.

    Article  CAS  PubMed  Google Scholar 

  48. Arsham AM, Howell JJ, Simon MC. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J Biol Chem. 2003;278(32):29655–60.

    Article  CAS  PubMed  Google Scholar 

  49. Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006;441(7092):437–43.

    Article  CAS  PubMed  Google Scholar 

  50. Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell. 2005;120(2):237–48.

    Article  CAS  PubMed  Google Scholar 

  51. Yoshioka A, Miyata H, Doki Y, Yamasaki M, Sohma I, Gotoh K, et al. LC3, an autophagosome marker, is highly expressed in gastrointestinal cancers. Int J Oncol. 2008;33(3):461–8.

    CAS  PubMed  Google Scholar 

  52. Lazova R, Klump V, Pawelek J. Autophagy in cutaneous malignant melanoma. J Cutan Pathol. 2010;37(2):256–68.

    Article  PubMed  Google Scholar 

  53. Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25(7):717–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rosich L, Xargay-Torrent S, Lopez-Guerra M, Campo E, Colomer D, Roue G. Counteracting autophagy overcomes resistance to everolimus in mantle cell lymphoma. Clin Cancer Res. 2012;18(19):5278–89.

    Article  CAS  PubMed  Google Scholar 

  55. Rosich L, Colomer D, Roue G. Autophagy controls everolimus (RAD001) activity in mantle cell lymphoma. Autophagy. 2013;9(1):115–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer. 2007;7(12):961–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Calabretta B, Salomoni P. Inhibition of autophagy: a new strategy to enhance sensitivity of chronic myeloid leukemia stem cells to tyrosine kinase inhibitors. Leuk Lymphoma. 2011;52(Suppl 1):54–9.

    Article  CAS  PubMed  Google Scholar 

  58. Watson AS, Mortensen M, Simon AK. Autophagy in the pathogenesis of myelodysplastic syndrome and acute myeloid leukemia. Cell Cycle. 2011;10(11):1719–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Helgason GV, Karvela M, Holyoake TL. Kill one bird with two stones: potential efficacy of BCR-ABL and autophagy inhibition in CML. Blood. 2011;118(8):2035–43.

    Article  CAS  PubMed  Google Scholar 

  60. Ekiz HA, Can G, Baran Y. Role of autophagy in the progression and suppression of leukemias. Crit Rev Oncol Hematol. 2012;81(3):275–85.

    Article  PubMed  Google Scholar 

  61. Sehgal AR, Konig H, Johnson DE, Tang D, Amaravadi RK, Boyiadzis M, et al. You eat what you are: autophagy inhibition as a therapeutic strategy in leukemia. Leukemia. 2015;29(3):517–25.

    Article  CAS  PubMed  Google Scholar 

  62. Auberger P, Puissant A. Autophagy, a key mechanism of oncogenesis and resistance in leukemia. Blood. 2017;129(5):547–52.

    Article  CAS  PubMed  Google Scholar 

  63. Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125(1):22–32.

    Article  CAS  PubMed  Google Scholar 

  64. Friedberg JW. How I treat double-hit lymphoma. Blood. 2017;130(5):590–6.

    Article  CAS  PubMed  Google Scholar 

  65. Reed JC. Bcl-2-family proteins and hematologic malignancies: history and future prospects. Blood. 2008;111(7):3322–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004;6(12):1221–8.

    Article  CAS  PubMed  Google Scholar 

  67. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005;122(6):927–39.

    Article  CAS  PubMed  Google Scholar 

  68. Brem EA, Thudium K, Khubchandani S, Tsai PC, Olejniczak SH, Bhat S, et al. Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas. Br J Haematol. 2011;153(5):599–611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nicotra G, Mercalli F, Peracchio C, Castino R, Follo C, Valente G, et al. Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas. Mod Pathol. 2010;23(7):937–50.

    Article  CAS  PubMed  Google Scholar 

  70. Huang JJ, Zhu YJ, Lin TY, Jiang WQ, Huang HQ, Li ZM. Beclin 1 expression predicts favorable clinical outcome in patients with diffuse large B-cell lymphoma treated with R-CHOP. Hum Pathol. 2011;42(10):1459–66.

    Article  CAS  PubMed  Google Scholar 

  71. Rohatgi RA, Shaw LM. An autophagy-independent function for Beclin 1 in cancer. Mol Cell Oncol. 2016;3(1):e1030539.

    Article  PubMed  CAS  Google Scholar 

  72. Xu F, Fang Y, Yan L, Xu L, Zhang S, Cao Y, et al. Nuclear localization of Beclin 1 promotes radiation-induced DNA damage repair independent of autophagy. Sci Rep. 2017;7:45385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. McCarthy A, Marzec J, Clear A, Petty RD, Coutinho R, Matthews J, et al. Dysregulation of autophagy in human follicular lymphoma is independent of overexpression of BCL-2. Oncotarget. 2014;5(22):11653–68.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Moreau P, Attal M, Facon T. Frontline therapy of multiple myeloma. Blood. 2015;125(20):3076–84.

    Article  CAS  PubMed  Google Scholar 

  75. Campo E, Rule S. Mantle cell lymphoma: evolving management strategies. Blood. 2015;125(1):48–55.

    Article  CAS  PubMed  Google Scholar 

  76. Jia L, Gopinathan G, Sukumar JT, Gribben JG. Blocking autophagy prevents bortezomib-induced NF-kappaB activation by reducing I-kappaBalpha degradation in lymphoma cells. PLoS One. 2012;7(2):e32584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Korolchuk VI, Mansilla A, Menzies FM, Rubinsztein DC. Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell. 2009;33(4):517–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bhalla S, Evens AM, Prachand S, Schumacker PT, Gordon LI. Paradoxical regulation of hypoxia inducible factor-1alpha (HIF-1alpha) by histone deacetylase inhibitor in diffuse large B-cell lymphoma. PLoS One. 2013;8(11):e81333.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Zang C, Eucker J, Liu H, Coordes A, Lenarz M, Possinger K, et al. Inhibition of pan-class I phosphatidyl-inositol-3-kinase by NVP-BKM120 effectively blocks proliferation and induces cell death in diffuse large B-cell lymphoma. Leuk Lymphoma. 2014;55(2):425–34.

    Article  CAS  PubMed  Google Scholar 

  80. Yuan H, He M, Cheng F, Bai R, da Silva SR, Aguiar RC, et al. Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy. Oncotarget. 2017;8(9):14912–24.

    PubMed  PubMed Central  Google Scholar 

  81. Inamdar AA, Goy A, Ayoub NM, Attia C, Oton L, Taruvai V, et al. Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents. Oncotarget. 2016;7(30):48692–731.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Tucker D, Rule S. Novel agents in mantle cell lymphoma. Expert Rev Anticancer Ther. 2017;17(6):491–506.

    Article  CAS  PubMed  Google Scholar 

  83. Gera JF, Mellinghoff IK, Shi Y, Rettig MB, Tran C, Hsu JH, et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem. 2004;279(4):2737–46.

    Article  CAS  PubMed  Google Scholar 

  84. Dal Col J, Dolcetti R. GSK-3beta inhibition: at the crossroad between Akt and mTOR constitutive activation to enhance cyclin D1 protein stability in mantle cell lymphoma. Cell Cycle. 2008;7(18):2813–6.

    Article  Google Scholar 

  85. Averous J, Fonseca BD, Proud CG. Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1. Oncogene. 2008;27(8):1106–13.

    Article  CAS  PubMed  Google Scholar 

  86. Easton JB, Houghton PJ. mTOR and cancer therapy. Oncogene. 2006;25(48):6436–46.

    Article  CAS  PubMed  Google Scholar 

  87. Hipp S, Ringshausen I, Oelsner M, Bogner C, Peschel C, Decker T. Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. Haematologica. 2005;90(10):1433–4.

    CAS  PubMed  Google Scholar 

  88. Dal Col J, Zancai P, Terrin L, Guidoboni M, Ponzoni M, Pavan A, et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood. 2008;111(10):5142–51.

    Article  CAS  Google Scholar 

  89. Yazbeck VY, Buglio D, Georgakis GV, Li Y, Iwado E, Romaguera JE, et al. Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma. Exp Hematol. 2008;36(4):443–50.

    Article  CAS  PubMed  Google Scholar 

  90. Cagnol S, Chambard JC. ERK and cell death: mechanisms of ERK-induced cell death–apoptosis, autophagy and senescence. FEBS J. 2010;277(1):2–21.

    Article  CAS  PubMed  Google Scholar 

  91. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, et al. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332(6036):1429–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Sivaprasad U, Basu A. Inhibition of ERK attenuates autophagy and potentiates tumour necrosis factor-alpha-induced cell death in MCF-7 cells. J Cell Mol Med. 2008;12(4):1265–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Martinez-Lopez N, Athonvarangkul D, Mishall P, Sahu S, Singh R. Autophagy proteins regulate ERK phosphorylation. Nat Commun. 2013;4:2799.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Martinez-Lopez N, Singh R. ATGs: scaffolds for MAPK/ERK signaling. Autophagy. 2014;10(3):535–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Dupere-Richer D, Kinal M, Menasche V, Nielsen TH, Del Rincon S, Pettersson F, et al. Vorinostat-induced autophagy switches from a death-promoting to a cytoprotective signal to drive acquired resistance. Cell Death Dis. 2013;4:e486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Torgersen ML, Engedal N, Boe SO, Hokland P, Simonsen A. Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells. Blood. 2013;122(14):2467–76.

    Article  CAS  PubMed  Google Scholar 

  97. Alinari L, Mahoney E, Patton J, Zhang X, Huynh L, Earl CT, et al. FTY720 increases CD74 expression and sensitizes mantle cell lymphoma cells to milatuzumab-mediated cell death. Blood. 2011;118(26):6893–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Alinari L, Baiocchi RA, Praetorius-Ibba M. FTY720-induced blockage of autophagy enhances anticancer efficacy of milatuzumab in mantle cell lymphoma: is FTY720 the next autophagy-blocking agent in lymphoma treatment? Autophagy. 2012;8(3):416–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Xiao Y, Guan J. 17-AAG enhances the cytotoxicity of flavopiridol in mantle cell lymphoma via autophagy suppression. Neoplasma. 2015;62(3):391–7.

    Article  CAS  PubMed  Google Scholar 

  100. Mastorci K, Montico B, Fae DA, Sigalotti L, Ponzoni M, Inghirami G, et al. Phospholipid scramblase 1 as a critical node at the crossroad between autophagy and apoptosis in mantle cell lymphoma. Oncotarget. 2016;7(27):41913–28.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Zhang H, Chen Z, Neelapu SS, Romaguera J, McCarty N. Hedgehog inhibitors selectively target cell migration and adhesion of mantle cell lymphoma in bone marrow microenvironment. Oncotarget. 2016;7(12):14350–65.

    PubMed  PubMed Central  Google Scholar 

  102. Lock R, Roy S, Kenific CM, Su JS, Salas E, Ronen SM, et al. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell. 2011;22(2):165–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 2011;25(5):460–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gayle S, Landrette S, Beeharry N, Conrad C, Hernandez M, Beckett P, et al. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. 2017;129(13):1768–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Alinari L. Toward autophagy-targeted therapy in lymphoma. Blood. 2017;129(13):1740–2.

    Article  CAS  PubMed  Google Scholar 

  106. Blum KA, Lozanski G, Byrd JC. Adult Burkitt leukemia and lymphoma. Blood. 2004;104(10):3009–20.

    Article  CAS  PubMed  Google Scholar 

  107. Cai Q, Medeiros LJ, Xu X, Young KH. MYC-driven aggressive B-cell lymphomas: biology, entity, differential diagnosis and clinical management. Oncotarget. 2015;6(36):38591–616.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Nguyen L, Papenhausen P, Shao H. The role of c-MYC in B-cell lymphomas: diagnostic and molecular aspects. Genes (Basel). 2017;8(4):116.

    Article  CAS  Google Scholar 

  109. Maclean KH, Dorsey FC, Cleveland JL, Kastan MB. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest. 2008;118(1):79–88.

    Article  CAS  PubMed  Google Scholar 

  110. Dang CV. Antimalarial therapy prevents Myc-induced lymphoma. J Clin Invest. 2008;118(1):15–7.

    Article  CAS  PubMed  Google Scholar 

  111. Hart LS, Cunningham JT, Datta T, Dey S, Tameire F, Lehman SL, et al. ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest. 2012;122(12):4621–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Dey S, Tameire F, Koumenis C. PERK-ing up autophagy during MYC-induced tumorigenesis. Autophagy. 2013;9(4):612–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pujals A, Favre L, Pioche-Durieu C, Robert A, Meurice G, Le Gentil M, et al. Constitutive autophagy contributes to resistance to TP53-mediated apoptosis in Epstein–Barr virus-positive latency III B-cell lymphoproliferations. Autophagy. 2015;11(12):2275–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. De Leo A, Colavita F, Ciccosanti F, Fimia GM, Lieberman PM, Mattia E. Inhibition of autophagy in EBV-positive Burkitt’s lymphoma cells enhances EBV lytic genes expression and replication. Cell Death Dis. 2015;6:e1876.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Rowe M, Kelly GL, Bell AI, Rickinson AB. Burkitt’s lymphoma: the Rosetta Stone deciphering Epstein–Barr virus biology. Semin Cancer Biol. 2009;19(6):377–88.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Cloonan SM, Williams DC. The antidepressants maprotiline and fluoxetine induce Type II autophagic cell death in drug-resistant Burkitt’s lymphoma. Int J Cancer. 2011;128(7):1712–23.

    Article  CAS  PubMed  Google Scholar 

  117. Turzanski J, Daniels I, Haynes AP. Involvement of macroautophagy in the caspase-independent killing of Burkitt lymphoma cell lines by rituximab. Br J Haematol. 2009;145(1):137–40.

    Article  CAS  PubMed  Google Scholar 

  118. Gu L, Xie L, Zuo C, Ma Z, Zhang Y, Zhu Y, et al. Targeting mTOR/p70S6K/glycolysis signaling pathway restores glucocorticoid sensitivity to 4E-BP1 null Burkitt Lymphoma. BMC Cancer. 2015;15:529.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Ni Z, Dai X, Wang B, Ding W, Cheng P, Xu L, et al. Natural Bcl-2 inhibitor (−)- gossypol induces protective autophagy via reactive oxygen species-high mobility group box 1 pathway in Burkitt lymphoma. Leuk Lymphoma. 2013;54(10):2263–8.

    Article  CAS  PubMed  Google Scholar 

  120. Re D, Thomas RK, Behringer K, Diehl V. From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential. Blood. 2005;105(12):4553–60.

    Article  CAS  PubMed  Google Scholar 

  121. Oehadian A, Koide N, Hassan F, Islam S, Mori I, Yoshida T, et al. Differential expression of autophagy in Hodgkin lymphoma cells treated with various anti-cancer drugs. Acta Med Indones. 2007;39(4):153–6.

    PubMed  Google Scholar 

  122. Guidetti A, Carlo-Stella C, Locatelli SL, Malorni W, Pierdominici M, Barbati C, et al. Phase II study of sorafenib in patients with relapsed or refractory lymphoma. Br J Haematol. 2012;158(1):108–19.

    Article  CAS  PubMed  Google Scholar 

  123. Klein JM, Henke A, Sauer M, Bessler M, Reiners KS, Engert A, et al. The histone deacetylase inhibitor LBH589 (panobinostat) modulates the crosstalk of lymphocytes with Hodgkin lymphoma cell lines. PLoS One. 2013;8(11):e79502.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Pierdominici M, Maselli A, Locatelli SL, Ciarlo L, Careddu G, Patrizio M, et al. Estrogen receptor beta ligation inhibits Hodgkin lymphoma growth by inducing autophagy. Oncotarget. 2017;8(5):8522–35.

    Article  PubMed  Google Scholar 

  125. Birkenmeier K, Moll K, Newrzela S, Hartmann S, Drose S, Hansmann ML. Basal autophagy is pivotal for Hodgkin and Reed–Sternberg cells’ survival and growth revealing a new strategy for Hodgkin lymphoma treatment. Oncotarget. 2016;7(29):46579–88.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Yoshida GJ. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. J Hematol Oncol. 2017;10(1):67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Vogl DT, Stadtmauer EA, Tan KS, Heitjan DF, Davis LE, Pontiggia L, et al. Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy. 2014;10(8):1380–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W, et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res. 2011;17(4):654–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650031, Yunnan, China

    Han Zhang

Authors
  1. Han Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Han Zhang.

Ethics declarations

Conflict of interest

The author has nothing to disclose.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, H. Targeting autophagy in lymphomas: a double-edged sword?. Int J Hematol 107, 502–512 (2018). https://doi.org/10.1007/s12185-018-2414-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-018-2414-6

Keywords

Search

Navigation