Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Oncosis and apoptosis induction by activation of an overexpressed ion channel in breast cancer cells


The critical role of calcium signalling in processes related to cancer cell proliferation and invasion has seen a focus on pharmacological inhibition of overexpressed ion channels in specific cancer subtypes as a potential therapeutic approach. However, despite the critical role of calcium in cell death pathways, pharmacological activation of overexpressed ion channels has not been extensively evaluated in breast cancer. Here we define the overexpression of transient receptor potential vanilloid 4 (TRPV4) in a subgroup of breast cancers of the basal molecular subtype. We also report that pharmacological activation of TRPV4 with GSK1016790A reduced viability of two basal breast cancer cell lines with pronounced endogenous overexpression of TRPV4, MDA-MB-468 and HCC1569. Pharmacological activation of TRPV4 produced pronounced cell death through two mechanisms: apoptosis and oncosis in MDA-MB-468 cells. Apoptosis was associated with PARP-1 cleavage and oncosis was associated with a rapid decline in intracellular ATP levels, which was a consequence of, rather than the cause of, the intracellular ion increase. TRPV4 activation also resulted in reduced tumour growth in vivo. These studies define a novel therapeutic strategy for breast cancers that overexpress specific calcium permeable plasmalemmal ion channels with available selective pharmacological activators.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6


  1. 1

    Aydar E, Yeo S, Djamgoz M, Palmer C . Abnormal expression, localization and interaction of canonical transient receptor potential ion channels in human breast cancer cell lines and tissues: a potential target for breast cancer diagnosis and therapy. Cancer Cell Int 2009; 9: 23.

    Article  Google Scholar 

  2. 2

    Ding X, He Z, Zhou K, Cheng J, Yao H, Lu D et al. Essential role of TRPC6 channels in G2/M phase transition and development of human glioma. J Natl Cancer Inst 2010; 102: 1052–1068.

    CAS  Article  Google Scholar 

  3. 3

    Zhuang L, Peng JB, Tou L, Takanaga H, Adam RM, Hediger MA et al. Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies. Lab Invest 2002; 82: 1755–1764.

    CAS  Article  Google Scholar 

  4. 4

    Yang SL, Cao Q, Zhou KC, Feng YJ, Wang YZ . Transient receptor potential channel C3 contributes to the progression of human ovarian cancer. Oncogene 2009; 28: 1320–1328.

    CAS  Article  Google Scholar 

  5. 5

    Czifra G, Varga A, Nyeste K, Marincsak R, Toth BI, Kovacs I et al. Increased expressions of cannabinoid receptor-1 and transient receptor potential vanilloid-1 in human prostate carcinoma. J Cancer Res Clin Oncol 2009; 135: 507–514.

    CAS  Article  Google Scholar 

  6. 6

    Monteith GR, Davis FM, Roberts-Thomson SJ . Calcium channels and pumps in cancer: changes and consequences. J Biol Chem 2012; 287: 31666–31673.

    CAS  Article  Google Scholar 

  7. 7

    Chen R, Zeng X, Zhang R, Huang J, Kuang X, Yang J et al. Cav1.3 channel alpha1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers. Urol Oncol 2014; 32: 524–536.

    CAS  Article  Google Scholar 

  8. 8

    Peters AA, Simpson PT, Bassett JJ, Lee JM, Da Silva L, Reid LE et al. Calcium channel TRPV6 as a potential therapeutic target in estrogen receptor-negative breast cancer. Mol Cancer Ther 2012; 11: 2158–2168.

    CAS  Article  Google Scholar 

  9. 9

    Berridge MJ, Lipp P, Bootman MD . The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 2000; 1: 11–21.

    CAS  Article  Google Scholar 

  10. 10

    Berridge MJ, Bootman MD, Roderick HL . Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 2003; 4: 517–529.

    CAS  Article  Google Scholar 

  11. 11

    Dubois C, Vanden Abeele F, Lehen'kyi V, Gkika D, Guarmit B, Lepage G et al. Remodeling of channel-forming ORAI proteins determines an oncogenic switch in prostate cancer. Cancer Cell 2014; 26: 19–32.

    CAS  Article  Google Scholar 

  12. 12

    Feng M, Grice DM, Faddy HM, Nguyen N, Leitch S, Wang Y et al. Store-independent activation of Orai1 by SPCA2 in mammary tumors. Cell 2010; 143: 84–98.

    CAS  Article  Google Scholar 

  13. 13

    Middelbeek J, Kuipers AJ, Henneman L, Visser D, Eidhof I, van Horssen R et al. TRPM7 is required for breast tumor cell metastasis. Cancer Res 2012; 72: 4250–4261.

    CAS  Article  Google Scholar 

  14. 14

    Rivenbark AG, O'Connor SM, Coleman WB . Molecular and cellular heterogeneity in breast cancer: challenges for personalized medicine. Am J Pathol 2013; 183: 1113–1124.

    CAS  Article  Google Scholar 

  15. 15

    Yang S, Zhang JJ, Huang XY . Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. Cancer Cell 2009; 15: 124–134.

    CAS  Article  Google Scholar 

  16. 16

    Pinton P, Giorgi C, Siviero R, Zecchini E, Rizzuto R . Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene 2008; 27: 6407–6418.

    CAS  Article  Google Scholar 

  17. 17

    Trump BF, Berezesky IK, Chang SH, Phelps PC . The pathways of cell death: oncosis, apoptosis, and necrosis. Toxicol Pathol 1997; 25: 82–88.

    CAS  Article  Google Scholar 

  18. 18

    Majno G, Joris I . Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 1995; 146: 3–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Hartley DM, Kurth MC, Bjerkness L, Weiss JH, Choi DW . Glutamate receptor-induced 45Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration. J Neurosci 1993; 13: 1993–2000.

    CAS  Article  Google Scholar 

  20. 20

    Sattler R, Tymianski M . Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Mol Neurobiol 2001; 24: 107–129.

    CAS  Article  Google Scholar 

  21. 21

    Lee WH, Choong LY, Mon NN, Lu S, Lin Q, Pang B et al. TRPV4 regulates breast cancer cell extravasation, stiffness and actin cortex. Sci Rep 2016; 6: 27903.

    CAS  Article  Google Scholar 

  22. 22

    Franken J, Uvin P, De Ridder D, Voets T . TRP channels in lower urinary tract dysfunction. Br J Pharmacol 2014; 171: 2537–2551.

    CAS  Article  Google Scholar 

  23. 23

    Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S, Jian MY et al. An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med 2012; 4: 159ra148.

    Article  Google Scholar 

  24. 24

    Adapala RK, Thoppil RJ, Ghosh K, Cappelli HC, Dudley AC, Paruchuri S et al. Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy. Oncogene 2016; 35: 314–322.

    CAS  Article  Google Scholar 

  25. 25

    Thorneloe KS, Sulpizio AC, Lin Z, Figueroa DJ, Clouse AK, McCafferty GP et al. N-((1 S)-1-{[4-((2 S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I. J Pharmacol Exp Ther 2008; 326: 432–442.

    CAS  Article  Google Scholar 

  26. 26

    Jo AO, Lakk M, Frye AM, Phuong TT, Redmon SN, Roberts R et al. Differential volume regulation and calcium signaling in two ciliary body cell types is subserved by TRPV4 channels. Proc Natl Acad Sci USA 2016; 113: 3885–3890.

    CAS  Article  Google Scholar 

  27. 27

    Weerasinghe P, Buja LM . Oncosis: an important non-apoptotic mode of cell death. Exp Mol Pathol 2012; 93: 302–308.

    CAS  Article  Google Scholar 

  28. 28

    Del Nagro C, Xiao Y, Rangell L, Reichelt M, O'Brien T . Depletion of the central metabolite NAD leads to oncosis-mediated cell death. J Biol Chem 2014; 289: 35182–35192.

    CAS  Article  Google Scholar 

  29. 29

    Goldsby RA, Heytler PG . Uncoupling of oxidative phosphorylation by carbonyl cyanide phenylhydrazones. Ii. Effects of carbonyl cyanide M-chlorophenylhydrazone on mitochondrial respiration. Biochemistry 1963; 2: 1142–1147.

    CAS  Article  Google Scholar 

  30. 30

    Cardaci S, Desideri E, Ciriolo MR . Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug. J Bioenerg Biomembr 2012; 44: 17–29.

    CAS  Article  Google Scholar 

  31. 31

    Gradilone SA, Masyuk TV, Huang BQ, Banales JM, Lehmann GL, Radtke BN et al. Activation of Trpv4 reduces the hyperproliferative phenotype of cystic cholangiocytes from an animal model of ARPKD. Gastroenterology 2010; 139: 304–314 e302.

    CAS  Article  Google Scholar 

  32. 32

    Willette RN, Bao W, Nerurkar S, Yue TL, Doe CP, Stankus G et al. Systemic activation of the transient receptor potential vanilloid subtype 4 channel causes endothelial failure and circulatory collapse: part 2. J Pharmacol Exp Ther 2008; 326: 443–452.

    CAS  Article  Google Scholar 

  33. 33

    Garcia-Elias A, Mrkonjic S, Jung C, Pardo-Pastor C, Vicente R, Valverde MA . The TRPV4 channel. Handb Exp Pharmacol 2014; 222: 293–319.

    CAS  Article  Google Scholar 

  34. 34

    Laing RJ, Dhaka A . ThermoTRPs and pain. Neuroscientist 2016; 22: 171–187.

    CAS  Article  Google Scholar 

  35. 35

    Shi Y, Ding X, He ZH, Zhou KC, Wang Q, Wang YZ . Critical role of TRPC6 channels in G2 phase transition and the development of human oesophageal cancer. Gut 2009; 58: 1443–1450.

    CAS  Article  Google Scholar 

  36. 36

    El Boustany C, Bidaux G, Enfissi A, Delcourt P, Prevarskaya N, Capiod T . Capacitative calcium entry and transient receptor potential canonical 6 expression control human hepatoma cell proliferation. Hepatology 2008; 47: 2068–2077.

    CAS  Article  Google Scholar 

  37. 37

    Zhang L, Barritt GJ . Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer cells. Cancer Res 2004; 64: 8365–8373.

    CAS  Article  Google Scholar 

  38. 38

    Mahieu F, Owsianik G, Verbert L, Janssens A, De Smedt H, Nilius B et al. TRPM8-independent menthol-induced Ca2+ release from endoplasmic reticulum and Golgi. J Biol Chem 2007; 282: 3325–3336.

    CAS  Article  Google Scholar 

  39. 39

    Arundine M, Tymianski M . Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium 2003; 34: 325–337.

    CAS  Article  Google Scholar 

  40. 40

    Choi DW . Excitotoxic cell death. J Neurobiol 1992; 23: 1261–1276.

    CAS  Article  Google Scholar 

  41. 41

    Wojda U, Salinska E, Kuznicki J . Calcium ions in neuronal degeneration. IUBMB Life 2008; 60: 575–590.

    CAS  Article  Google Scholar 

  42. 42

    Zong WX, Thompson CB . Necrotic death as a cell fate. Genes Dev 2006; 20: 1–15.

    CAS  Article  Google Scholar 

  43. 43

    Berridge MJ, Bootman MD, Lipp P . Calcium—a life and death signal. Nature 1998; 395: 645–648.

    CAS  Article  Google Scholar 

  44. 44

    Frandsen SK, Gissel H, Hojman P, Tramm T, Eriksen J, Gehl J . Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis. Cancer Res 2012; 72: 1336–1341.

    CAS  Article  Google Scholar 

  45. 45

    Pollack JR, Sorlie T, Perou CM, Rees CA, Jeffrey SS, Lonning PE et al. Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc Natl Acad Sci USA 2002; 99: 12963–12968.

    CAS  Article  Google Scholar 

  46. 46

    Solvang HK, Lingjaerde OC, Frigessi A, Borresen-Dale AL, Kristensen VN . Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer. BMC Bioinformatics 2011; 12: 197.

    Article  Google Scholar 

  47. 47

    Cancer Genome Atlas N.. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490: 61–70.

    Article  Google Scholar 

  48. 48

    Klijn C, Durinck S, Stawiski EW, Haverty PM, Jiang Z, Liu H et al. A comprehensive transcriptional portrait of human cancer cell lines. Nat Biotechnol 2015; 33: 306–312.

    CAS  Article  Google Scholar 

  49. 49

    Li B, Dewey CN . RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform 2011; 12: 323.

    CAS  Article  Google Scholar 

  50. 50

    Langfelder P, Horvath S . WGCNA: an R package for weighted correlation network analysis. BMC Bioinform 2008; 9: 559.

    Article  Google Scholar 

  51. 51

    Clarke C, Madden SF, Doolan P, Aherne ST, Joyce H, O'Driscoll L et al. Correlating transcriptional networks to breast cancer survival: a large-scale coexpression analysis. Carcinogenesis 2013; 34: 2300–2308.

    CAS  Article  Google Scholar 

  52. 52

    Haas BE, Horvath S, Pietilainen KH, Cantor RM, Nikkola E, Weissglas-Volkov D et al. Adipose co-expression networks across Finns and Mexicans identify novel triglyceride-associated genes. BMC Med Genomics 2012; 5: 61.

    CAS  Article  Google Scholar 

  53. 53

    Presson AP, Yoon NK, Bagryanova L, Mah V, Alavi M, Maresh EL et al. Protein expression based multimarker analysis of breast cancer samples. BMC Cancer 2011; 11: 230.

    CAS  Article  Google Scholar 

  54. 54

    Eisen MB, Spellman PT, Brown PO, Botstein D . Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998; 95: 14863–14868.

    CAS  Article  Google Scholar 

  55. 55

    Aung CS, Ye W, Plowman G, Peters AA, Monteith GR, Roberts-Thomson SJ . Plasma membrane calcium ATPase 4 and the remodeling of calcium homeostasis in human colon cancer cells. Carcinogenesis 2009; 30: 1962–1969.

    CAS  Article  Google Scholar 

  56. 56

    Wu TT, Peters AA, Tan PT, Roberts-Thomson SJ, Monteith GR . Consequences of activating the calcium-permeable ion channel TRPV1 in breast cancer cells with regulated TRPV1 expression. Cell Calcium 2014; 56: 59–67.

    CAS  Article  Google Scholar 

  57. 57

    Curry MC, Luk NA, Kenny PA, Roberts-Thomson SJ, Monteith GR . Distinct regulation of cytoplasmic calcium signals and cell death pathways by different plasma membrane calcium ATPase isoforms in MDA-MB-231 breast cancer cells. J Biol Chem 2012; 287: 28598–28608.

    CAS  Article  Google Scholar 

  58. 58

    Azimi I, Beilby H, Davis FM, Marcial DL, Kenny PA, Thompson EW et al. Altered purinergic receptor-Ca(2)(+) signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells. Mol Oncol 2016; 10: 166–178.

    CAS  Article  Google Scholar 

Download references


This work was supported by the National Health and Medical Research Council of Australia (1079671) and Cancer Council Queensland (1042819). We are grateful to Sunil Lakhani and The Brisbane Breast Bank (The University of Queensland Centre for Clinical Research, Brisbane, Australia) for providing the MDA-MB-468 and BT-20 cell lines and RNA from 184A1, 184B5, MCF10A and Bre-80-hTERT cells for this study. GM is supported by the Mater Foundation. The Translational Research Institute is supported by a grant from the Australian Government. SYNJ was funded by the Ministry of Higher Education Malaysia Scholarship. ED is the recipient of a NBCF fellowship (ECR13-04).

Author information



Corresponding author

Correspondence to G R Monteith.

Ethics declarations

Competing interests

GRM and SJR-T are associated with QUE-Oncology Inc.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Peters, A., Jamaludin, S., Yapa, K. et al. Oncosis and apoptosis induction by activation of an overexpressed ion channel in breast cancer cells. Oncogene 36, 6490–6500 (2017).

Download citation

Further reading


Quick links