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Calcium Signaling and the Regulation of Chemosensitivity in Cancer Cells: Role of the Transient Receptor Potential Channels

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Book cover Calcium Signaling

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1131))

Abstract

Cancer cells acquire the ability to modify the calcium signaling network by altering the expression and functions of cation channels, pumps or transporters. Calcium signaling pathways are involved in proliferation, angiogenesis, invasion, immune evasion, disruption of cell death pathways, ECM remodelling, epithelial-mesenchymal transition (EMT) and drug resistance. Among cation channels, a pivotal role is played by the Transient Receptor Potential non-selective cation-permeable receptors localized in plasma membrane, endoplasmic reticulum, mitochondria and lysosomes. Several findings indicate that the dysregulation in calcium signaling induced by TRP channels is responsible for cancer growth, metastasis and chemoresistance. Drug resistance represents a major limitation in the application of current therapeutic regimens and several efforts are spent to overcome it. Here we describe the ability of Transient Receptor Potential Channels to modify, by altering the intracellular calcium influx, the cancer cell sensitivity to chemotherapeutic drugs.

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References

  1. Giorgi C, Danese A, Missiroli S, Patergnani S, Pinton P (2018) Calcium dynamics as a machine for decoding signals. Trends Cell Biol 28(4):258–273

    Article  CAS  PubMed  Google Scholar 

  2. Cui C, Merritt R, Fu L, Pan Z (2017) Targeting calcium signaling in cancer therapy. Acta Pharm Sin B 7(1):3–17

    Article  PubMed  Google Scholar 

  3. Zhang X, Yuan D, Sun Q, Xu L, Lee E, Lewis AJ, Zuckerbraun BS, Rosengart MR (2017) Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis. FASEB J 31(10):4382–4395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bootman MD, Chehab T, Bultynck G, Parys JB, Rietdorf K (2018) The regulation of autophagy by calcium signals: do we have a consensus? Cell Calcium 70:32–46

    Article  CAS  PubMed  Google Scholar 

  5. Busselberg D, Florea AM (2017) Targeting intracellular calcium signaling ([Ca2+]i) to overcome multiddrug resistance of cancer cells: a mini-overview. Cancers 9:48

    Article  PubMed Central  CAS  Google Scholar 

  6. Xu MM, Seas A, Kijan M, Ji KSY, Bell HN (2018) A temporal examination of calcium signaling in cancer-from tumorigenesis, to immune evasion, and metastasis. Cell Biosci 8:25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. La Rovere RM, Roest G, Bultynck G, Parys JB (2016) Intracellular Ca2+ signaling and Ca2+ microdomains in the control of cell survival, apoptosis and autophagy. Cell Calcium 60(2):74–87

    Article  PubMed  CAS  Google Scholar 

  8. Nilius B, Owsianik G (2011) The transient receptor potential family of ion channels. Genome Biol 12(3):218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shapovalov G, Ritaine A, Skryma R, Prevarskaya N (2016) Role of TRP ion channels in cancer and tumorigenesis. Semin Immunopathol 38(3):357–369

    Article  CAS  PubMed  Google Scholar 

  10. Gautier M, Dhennin-Duthille I, Ay AS, Rybarczyk P, Korichneva I, Ouadid-Ahidouch H (2014) New insights into pharmacological tools to TR(i)P cancer up. Br J Pharmacol 171:2582–2592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Litan A, Langhans SA (2015) Cancer as a channelopathy: ion channels and pumps in tumor development and progression. Front Cell Neurosci 9:86

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Santoni G, Farfariello V, Amantini C (2011) TRPV channels in tumor growth and progression. Adv Exp Med Biol 704:947–967

    Article  CAS  PubMed  Google Scholar 

  13. Santoni G, Farfariello V (2011) TRP channels and cancer: new targets for diagnosis and chemotherapy. Endocr Metab Immune Disord Drug Targets 11:54–67

    Article  CAS  PubMed  Google Scholar 

  14. Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S (2014) Drug resistance in cancer: an overview. Cancers (Basel) 6:1769–1792

    Article  CAS  Google Scholar 

  15. Michael M, Doherty MM (2005) Tumoral drug metabolism: overview and its implications for cancer therapy. J Clin Oncol 23:205–229

    Article  CAS  PubMed  Google Scholar 

  16. Stavrovskaya AA (2000) Cellular mechanisms of multidrug resistance of tumor cells. Biochemistry (Mosc) 65:95–106

    CAS  Google Scholar 

  17. He DX, Ma X (2016) Transient receptor potential channel C5 in cancer chemoresistance. Acta Pharmacol Sin 37:19–24

    Article  CAS  PubMed  Google Scholar 

  18. Binkhathlan Z, Lavasanifar A (2013) P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer: current status and future perspectives. Curr Cancer Drug Targets 13:326–346

    Article  CAS  PubMed  Google Scholar 

  19. Ma X, Cai Y, He D, Zou C, Zhang P, Lo CY, Xu Z, Chan FL, Yu S, Chen Y, Zhu R, Lei J, Jin J, Yao X (2012) Transient receptor potential channel TRPC5 is essential for P-glycoprotein induction in drug-resistant cancer cells. Proc Natl Acad Sci U S A 109:16282–16287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. He DX, Gu XT, Jiang L, Jin J, Ma X (2014) A methylation-based regulatory network for microRNA 320a in chemoresistant breast cancer. Mol Pharmacol 86:536–547

    Article  PubMed  CAS  Google Scholar 

  21. Xu R, Rai A, Chen M, Suwakulsiri W, Greening DW, Simpson RJ (2018) Extracellular vesicles in cancer – implications for future improvements in cancer care. Nat Rev Clin Oncol 15(10):617–638. https://doi.org/10.1038/s41571-018-0036-9

    Article  CAS  PubMed  Google Scholar 

  22. Ma X, Chen Z, Hua D, He D, Wang L, Zhang P, Wang J, Cai Y, Gao C, Zhang X, Zhang F, Wang T, Hong T, Jin L, Qi X, Chen S, Gu X, Yang D, Pan Q, Zhu Y, Chen Y, Chen D, Jiang L, Han X, Zhang Y, Jin J, Yao X (2014) Essential role for TrpC5-containing extracellular vesicles in breast cancer with chemotherapeutic resistance. Proc Natl Acad Sci U S A 111:6389–6394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang T, Ning K, Lu TX, Sun X, Jin L, Qi X, Jin J, Hua D (2017) Increasing circulating exosomes-carrying TRPC5 predicts chemoresistance in metastatic breast cancer patients. Cancer Sci 108:448–454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dong Y, Pan Q, Jiang L, Chen Z, Zhang F, Liu Y, Xing H, Shi M, Li J, Li X, Zhu Y, Chen Y, Bruce IC, Jin J, Ma X (2014) Tumor endothelial expression of P-glycoprotein upon microvesicular transfer of TrpC5 derived from adriamycin-resistant breast cancer cells. Biochem Biophys Res Commun 446:85–90

    Article  CAS  PubMed  Google Scholar 

  25. Singh SS, Vats S, Chia AY, Tan TZ, Deng S, Ong MS, Arfuso F, Yap CT, Goh BC, Sethi G, Huang RY, Shen HM, Manjithaya R, Kumar AP (2018) Dual role of autophagy in hallmarks of cancer. Oncogene 37:1142–1158

    Article  CAS  PubMed  Google Scholar 

  26. Sukumaran P, Schaar A, Sun Y, Singh BB (2016) Functional role of TRP channels in modulating ER stress and autophagy. Cell Calcium 60:123–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang P, Liu X, Li H, Chen Z, Yao X, Jin J, Ma X (2017) TRPC5-induced autophagy promotes drug resistance in breast carcinoma via CaMKKβ/AMPKα/mTOR pathway. Sci Rep 7(1):3158

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Wang T, Chen Z, Zhu Y, Pan Q, Liu Y, Qi X, Jin L, Jin J, Ma X, Hua D (2015) Inhibition of transient receptor potential channel 5 reverses 5-fluorouracil resistance in human colorectal Cancer cells. J Biol Chem 290:448–456

    Article  CAS  PubMed  Google Scholar 

  29. Wang T, Ning K, Lu TX, Hua D (2017) Elevated expression of TrpC5 and GLUT1 is associated with chemoresistance in colorectal cancer. Oncol Rep 37:1059–1065

    Article  CAS  PubMed  Google Scholar 

  30. Wang T, Ning K, Sun X, Zhang C, Jin L-f, Hua D (2018) Glycolysis is essential for chemoresistance induced by transient receptor potential channel C5 in colorectal cancer. BMC Cancer 18:207

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Bhatia S, Monkman J, Toh AKL, Nagaraj SH, Thompson EW (2017) Targeting epithelial-mesenchymal plasticity in cancer: clinical and preclinical advances in therapy and monitoring. Biochem J 474:3269–3306

    Article  CAS  PubMed  Google Scholar 

  32. Wen L, Liang C, Chen E, Chen W, Liang F, Zhi X, Wei T, Xue F, Li G, Yang Q, Gong W, Feng X, Bai X, Liang T (2016) Regulation of multi-drug resistance in hepatocellular carcinoma cells is TRPC6/calcium dependent. Sci Rep 6:23269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sander P, Mostafa H, Soboh A, Schneider JM, Pala A, Baron AK, Moepps B, Wirtz CR, Georgieff M, Schneider M (2017) Vacquinol-1 inducible cell death in glioblastoma multiforme is counter regulated by TRPM7 activity induced by exogenous ATP. Oncotarget 8:35124–35137

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yee NS, Zhou W, Lee M, Yee RK (2012) Targeted silencing of TRPM7 ion channel induces replicative senescence and produces enhanced cytotoxicity with gemcitabine in pancreatic adenocarcinoma. Cancer Lett 318:99–105

    Article  CAS  PubMed  Google Scholar 

  35. Du GJ, Li JH, Liu WJ, Liu YH, Zhao B, Li HR, Hou XD, Li H, Qi XX, Duan YJ (2014) The combination of TRPM8 and TRPA1 expression causes an invasive phenotype in lung cancer. Tumour Biol 35:1251–1261

    Article  CAS  PubMed  Google Scholar 

  36. Yu S, Xu Z, Zou C, Wu D, Wang Y, Yao X, Ng CF, Chan FL (2014) Ion channel TRPM8 promotes hypoxic growth of prostate cancer cells via an O2 -independent and RACK1-mediated mechanism of HIF-1α stabilization. J Pathol 234:514–525

    Article  CAS  PubMed  Google Scholar 

  37. Wang Y, Yang Z, Meng Z, Cao H, Zhu G, Liu T, Wang X (2013) Knockdown of TRPM8 suppresses cancer malignancy and enhances epirubicin-induced apoptosis in human osteosarcoma cells. Int J Biol Sci 10:90–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mergler S, Cheng Y, Skosyrski S, Garreis F, Pietrzak P, Kociok N, Dwarakanath A, Reinach PS, Kakkassery V (2012) Altered calcium regulation by thermosensitive transient receptor potential channels in etoposide-resistant WERI-Rb1 retinoblastoma cells. Exp Eye Res 94:157–173

    Article  CAS  PubMed  Google Scholar 

  39. Nur G, Nazıroğlu M, Deveci HA (2017) Synergic prooxidant, apoptotic and TRPV1 channel activator effects of alpha-lipoic acid and cisplatin in MCF-7 breast cancer cells. J Recept Signal Transduct Res 37:569–577

    Article  CAS  PubMed  Google Scholar 

  40. Nabissi M, Morelli MB, Amantini C, Farfariello V, Ricci-Vitiani L, Caprodossi S, Arcella A, Santoni M, Giangaspero F, De Maria R, Santoni G (2010) TRPV2 channel negatively controls glioma cell proliferation and resistance to Fas-induced apoptosis in ERK-dependent manner. Carcinogenesis 31(5):794–803

    Article  CAS  PubMed  Google Scholar 

  41. Nabissi M, Morelli MB, Santoni M, Santoni G (2013) Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 34:48–57

    Article  CAS  PubMed  Google Scholar 

  42. Nabissi M, Morelli MB, Amantini C, Liberati S, Santoni M, Ricci-Vitiani L, Pallini R, Santoni G (2015) Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner. Int J Cancer 137:1855–1869

    Article  CAS  PubMed  Google Scholar 

  43. Morelli MB, Nabissi M, Amantini C, Farfariello V, Ricci-Vitiani L, di Martino S, Pallini R, Larocca LM, Caprodossi S, Santoni M, De Maria R, Santoni G (2012) The transient receptor potential vanilloid-2 cation channel impairs glioblastoma stem-like cell proliferation and promotes differentiation. Int J Cancer 131:E1067–E1077

    Article  CAS  PubMed  Google Scholar 

  44. Peters AA, Simpson PT, Bassett JJ, Lee JM, Da Silva L, Reid LE, Song S, Parat MO, Lakhani SR, Kenny PA, Roberts-Thomson SJ, Monteith GR (2012) Calcium channel TRPV6 as a potential therapeutic target in estrogen receptor-negative breast cancer. Mol Cancer Ther 11:2158–2168

    Article  CAS  PubMed  Google Scholar 

  45. Bolanz KA, Kovacs GG, Landowski CP, Hediger MA (2009) Tamoxifen inhibits TRPV6 activity via estrogen receptor-independent pathways in TRPV6-expressing MCF-7 breast cancer cells. Mol Cancer Res 7:2000–2010

    Article  CAS  PubMed  Google Scholar 

  46. Bolanz KA, Hediger MA, Landowski CP (2008) The role of TRPV6 in breast carcinogenesis. Mol Cancer Ther 7:271–279

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. School of Pharmacy, Immunopathology and Molecular Medicine Laboratory, University of Camerino, Camerino, Italy

    Giorgio Santoni, Maria Beatrice Morelli, Oliviero Marinelli & Massimo Nabissi

  2. School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy

    Maria Beatrice Morelli, Oliviero Marinelli & Consuelo Amantini

  3. Clinic and Oncology Unit, Macerata Hospital, Macerata, Italy

    Matteo Santoni

Authors
  1. Giorgio Santoni
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  2. Maria Beatrice Morelli
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  3. Oliviero Marinelli
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  4. Massimo Nabissi
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  5. Matteo Santoni
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  6. Consuelo Amantini
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Corresponding author

Correspondence to Consuelo Amantini .

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Editors and Affiliations

  1. Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden

    Md. Shahidul Islam

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Santoni, G., Morelli, M.B., Marinelli, O., Nabissi, M., Santoni, M., Amantini, C. (2020). Calcium Signaling and the Regulation of Chemosensitivity in Cancer Cells: Role of the Transient Receptor Potential Channels. In: Islam, M. (eds) Calcium Signaling. Advances in Experimental Medicine and Biology, vol 1131. Springer, Cham. https://doi.org/10.1007/978-3-030-12457-1_20

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