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Transient receptor potential channel C3 contributes to the progression of human ovarian cancer

Oncogene volume 28, pages 1320–1328 (2009)Cite this article

Abstract

Ovarian cancer (OC) is the leading cause of death from gynecological malignancy. However, the mechanism by which OC develops remains largely unknown. Increases in cytosolic free Ca2+ ([Ca2+]i) can result in different physiological changes including cell growth, differentiation and death. The transient receptor potential (TRP) C channels are nonselective cation channels with permeability to Ca2+. Here we report that TRPC3 channels promote human OC growth. The TRPC3 protein levels in human OC specimens were greatly increased than those in normal ovarian specimens. Downregulating TRPC3 expression in SKOV3 cells, a human OC cell line, led to reduction of proliferation, suppression in epidermal growth factor-induced Ca2+ influx, dephosphorylation of Cdc2 and CaMKIIα and prolonged progression through M phase of these cells. Further, decreased the expression of TRPC3 suppressed the tumor formation generated by injecting SKOV3 cells in nude mice. Together, our results suggest that increased activity of TRPC3 channels is necessary for the development of OCs.

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References

  • Auersperg N, Edelson MI, Mok SC, Johnson SW, Hamilton TC . (1998). The biology of ovarian cancer. Semin Oncol 25: 281–304.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Bezzerides VJ, Ramsey IS, Kotecha S, Greka A, Clapham DE . (2004). Rapid vesicular translocation and insertion of TRP channels. Nat Cell Biol 6: 709–720.

    Article  CAS  PubMed  Google Scholar 

  • Brummelkamp TR, Bernards R, Agami R . (2002). A system for stable expression of short interfering RNAs in mammalian cells. Science 296: 550–553.

    Article  CAS  PubMed  Google Scholar 

  • Clapham DE, Runnels LW, Strubing C . (2001). The trp ion channel family. Nat Rev Neurosci 2: 387–396.

    Article  CAS  PubMed  Google Scholar 

  • Cook SJ, Lockyer PJ . (2006). Recent advances in Ca2+-dependent Ras regulation and cell proliferation. Cell Calcium 39: 101–112.

    Article  CAS  PubMed  Google Scholar 

  • Cullen PJ, Lockyer PJ . (2002). Integration of calcium and RAS signalling. Nat Rev Mol Cell Biol 3: 339–348.

    Article  CAS  PubMed  Google Scholar 

  • Dietrich A, Mederos YSM, Gollasch M, Gross V, Storch U, Dubrovska G et al. (2005). Increased vascular smooth muscle contractility in TRPC6−/− mice. Mol Cell Biol 25: 6980–6989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dolmetsch RE, Xu K, Lewis RS . (1998). Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392: 933–936.

    Article  CAS  PubMed  Google Scholar 

  • Eder P, Poteser M, Romanin C, Groschner K . (2005). Na(+) entry and modulation of Na(+)/Ca(2+) exchange as a key mechanism of TRPC signaling. Pflugers Arch 451: 99–104.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Fong YL, Taylor WL, Means AR, Soderling TR . (1989). Studies of the regulatory mechanism of Ca2+/calmodulin-dependent protein kinase II. Mutation of threonine 286 to alanine and aspartate. J Biol Chem 264: 16759–16763.

    CAS  PubMed  Google Scholar 

  • Hansen DV, Tung JJ, Jackson PK . (2006). CaMKII and Polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. Proc Natl Acad Sci USA 103: 608–613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G . (1999). Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397: 259–263.

    Article  CAS  PubMed  Google Scholar 

  • Hurst RS, Zhu X, Boulay G, Birnbaumer L, Stefani E . (1998). Ionic currents underlying HTRP3 mediated agonist-dependent Ca2+ influx in stably transfected HEK293 cells. FEBS Lett 422: 333–338.

    Article  CAS  PubMed  Google Scholar 

  • Hussain MM, Kotz H, Minasian L, Premkumar A, Sarosy G, Reed E et al. (2003). Phase II trial of carboxyamidotriazole in patients with relapsed epithelial ovarian cancer. J Clin Oncol 21: 4356–4363.

    Article  CAS  PubMed  Google Scholar 

  • Jia Y, Zhou J, Tai Y, Wang Y . (2007). TRPC channels promote cerebellar granule neuron survival. Nat Neurosci 10: 559–567.

    Article  CAS  PubMed  Google Scholar 

  • Kahl CR, Means AR . (2003). Regulation of cell cycle progression by calcium/calmodulin-dependent pathways. Endocr Rev 24: 719–736.

    Article  CAS  PubMed  Google Scholar 

  • Kao JP, Alderton JM, Tsien RY, Steinhardt RA . (1990). Active involvement of Ca2+ in mitotic progression of Swiss 3T3 fibroblasts. J Cell Biol 111: 183–196.

    Article  CAS  PubMed  Google Scholar 

  • Kohn EC, Reed E, Sarosy G, Christian M, Link CJ, Cole K et al. (1996). Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers. Cancer Res 56: 569–573.

    CAS  PubMed  Google Scholar 

  • Lintschinger B, Balzer-Geldsetzer M, Baskaran T, Graier WF, Romanin C, Zhu MX et al. (2000). Coassembly of Trp1 and Trp3 proteins generates Diacylglycerol- and Ca2+-sensitive cation channels. J Biol Chem 275: 27799–27805.

    CAS  PubMed  Google Scholar 

  • Liu J, Maller JL . (2005). Calcium elevation at fertilization coordinates phosphorylation of XErp1/Emi2 by Plx1 and CaMK II to release metaphase arrest by cytostatic factor. Current Biology 15: 1458–1468.

    Article  CAS  PubMed  Google Scholar 

  • Lorca T, Cruzalegui FH, Fesquet D, Cavadore JC, Mery J, Means A et al. (1993). Calmodulin-dependent protein kinase II mediates inactivation of MPF and CSF upon fertilization of Xenopus eggs. Nature 366: 270–273.

    Article  CAS  PubMed  Google Scholar 

  • Maihle NJ, Baron AT, Barrette BA, Boardman CH, Christensen TA, Cora EM et al. (2002). EGF/ErbB receptor family in ovarian cancer. Cancer Treat Res 107: 247–258.

    CAS  PubMed  Google Scholar 

  • Minaguchi T, Waite KA, Eng C . (2006). Nuclear localization of PTEN is regulated by Ca2+ through a tyrosil phosphorylation-independent conformational modification in major vault protein. Cancer Res 66: 11677–11682.

    Article  CAS  PubMed  Google Scholar 

  • Mochida S, Hunt T . (2007). Calcineurin is required to release Xenopus egg extracts from meiotic M phase. Nature 449: 336–340.

    Article  CAS  PubMed  Google Scholar 

  • Monteith GR, McAndrew D, Faddy HM, Roberts-Thomson SJ . (2007). Calcium and cancer: targeting Ca2+ transport. Nat Rev Cancer 7: 519–530.

    Article  CAS  PubMed  Google Scholar 

  • Nicosia SV, Bai W, Cheng JQ, Coppola D, Kruk PA . (2003). Oncogenic pathways implicated in ovarian epithelial cancer. Hematol Oncol Clin North Am 17: 927–943.

    Article  PubMed  Google Scholar 

  • Odell AF, Scott JL, Van Helden DF . (2005). Epidermal growth factor induces tyrosine phosphorylation, membrane insertion, and activation of transient receptor potential channel 4. J Biol Chem 280: 37974–37987.

    Article  CAS  PubMed  Google Scholar 

  • Popper LD, Batra S . (1993). Calcium mobilization and cell proliferation activated by extracellular ATP in human ovarian tumour cells. Cell Calcium 14: 209–218.

    Article  CAS  PubMed  Google Scholar 

  • Psyrri A, Kassar M, Yu Z, Bamias A, Weinberger PM, Markakis S et al. (2005). Effect of epidermal growth factor receptor expression level on survival in patients with epithelial ovarian cancer. Clin Cancer Res 11: 8637–8643.

    Article  CAS  PubMed  Google Scholar 

  • Rauh NR, Schmidt A, Bormann J, Nigg EA, Mayer TU . (2005). Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation. Nature 437: 1048–1052.

    Article  CAS  PubMed  Google Scholar 

  • Roderick HL, Cook SJ . (2008). Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat Rev Cancer 8: 361–375.

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg P, Hawkins A, Stiber J, Shelton JM, Hutcheson K, Bassel-Duby R et al. (2004). TRPC3 channels confer cellular memory of recent neuromuscular activity. Proc Natl Acad Sci USA 101: 9387–9392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosker C, Graziani A, Lukas M, Eder P, Zhu MX, Romanin C et al. (2004). Ca2+ signaling by TRPC3 involves Na+ entry and local coupling to the Na+/Ca2+ exchanger. J Biol Chem 279: 13696–13704.

    Article  CAS  PubMed  Google Scholar 

  • Schultze-Mosgau A, Katzur AC, Arora KK, Stojilkovic SS, Diedrich K, Ortmann O . (2000). Characterization of calcium-mobilizing, purinergic P2Y2 receptors in human ovarian cancer cells. Mol Hum Reprod 6: 435–442.

    Article  CAS  PubMed  Google Scholar 

  • Smyth JT, Lemonnier L, Vazquez G, Bird GS, Putney Jr JW . (2006). Dissociation of regulated trafficking of TRPC3 channels to the plasma membrane from their activation by phospholipase C. J Biol Chem 281: 11712–11720.

    Article  CAS  PubMed  Google Scholar 

  • Thebault S, Flourakis M, Vanoverberghe K, Vandermoere F, Roudbaraki M, Lehen’kyi V et al. (2006). Differential role of transient receptor potential channels in Ca2+ entry and proliferation of prostate cancer epithelial cells. Cancer Res 66: 2038–2047.

    Article  CAS  PubMed  Google Scholar 

  • Thebault S, Zholos A, Enfissi A, Slomianny C, Dewailly E, Roudbaraki M et al. (2005). Receptor-operated Ca2+ entry mediated by TRPC3/TRPC6 proteins in rat prostate smooth muscle (PS1) cell line. J Cell Physiol 204: 320–328.

    Article  CAS  PubMed  Google Scholar 

  • Tombes RM, Borisy GG . (1989). Intracellular free calcium and mitosis in mammalian cells: anaphase onset is calcium modulated, but is not triggered by a brief transient. J Cell Biol 109: 627–636.

    Article  CAS  PubMed  Google Scholar 

  • Venkatachalam K, Montell C . (2007). TRP channels. Ann Rev Biochem 76: 387.

    Article  CAS  PubMed  Google Scholar 

  • Xu N, Luo KQ, Chang DC . (2003). Ca2+ signal blockers can inhibit M/A transition in mammalian cells by interfering with the spindle checkpoint. Biochem Biophys Res Commun 306: 737–745.

    Article  CAS  PubMed  Google Scholar 

  • Yang H, Mergler S, Sun X, Wang Z, Lu L, Bonanno JA et al. (2005). TRPC4 knockdown suppresses epidermal growth factor-induced store-operated channel activation and growth in human corneal epithelial cells. J Biol Chem 280: 32230–32237.

    Article  CAS  PubMed  Google Scholar 

  • Yu Y, Fantozzi I, Remillard CV, Landsberg JW, Kunichika N, Platoshyn O et al. (2004). Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc Natl Acad Sci USA 101: 13861–13866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu Y, Sweeney M, Zhang S, Platoshyn O, Landsberg J, Rothman A et al. (2003). PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Am J Physiol Cell Physiol 284: C316–C330.

    Article  CAS  PubMed  Google Scholar 

  • Zagranichnaya TK, Wu X, Villereal ML . (2005). Endogenous TRPC1, TRPC3, and TRPC7 proteins combine to form native store-operated channels in HEK-293 cells. J Biol Chem 280: 29559–29569.

    Article  CAS  PubMed  Google Scholar 

  • Zhu X, Jiang M, Birnbaumer L . (1998). Receptor-activated Ca2+ influx via human Trp3 stably expressed in human embryonic kidney (HEK)293 cells. Evidence for a non-capacitative Ca2+ entry. J Biol Chem 273: 133–142.

    Article  CAS  PubMed  Google Scholar 

  • Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E et al. (1996). trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell 85: 661–671.

    Article  CAS  PubMed  Google Scholar 

  • Zitt C, Obukhov AG, Strubing C, Zobel A, Kalkbrenner F, Luckhoff A et al. (1997). Expression of TRPC3 in Chinese hamster ovary cells results in calcium-activated cation currents not related to store depletion. J Cell Biol 138: 1333–1341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Q Hu and HL Yao for technical support and B Shen for reading the article. This work was supported by grants from the 973 Program (2006CB806600), projects 30711120566, 30621062, U0632006 from the National Natural Science Foundation of China and project B117 from Shanghai Leading Academic Discipline Project.

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Authors and Affiliations

  1. Laboratory of Neural Signal Transduction, Institute of Neuroscience, Shanghai Institutes of Biological Sciences, State Key Laboratory of Neuroscience, Shanghai, China

    S L Yang, K C Zhou & Y Z Wang

  2. The Graduate School, Chinese Academy of Science, Shanghai, China

    S L Yang, K C Zhou & Y Z Wang

  3. The Obstetrics and Gynecology Hospital of Medical Center, Fudan University, Shanghai, China

    Q Cao & Y J Feng

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Correspondence to Y Z Wang.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Yang, S., Cao, Q., Zhou, K. et al. Transient receptor potential channel C3 contributes to the progression of human ovarian cancer. Oncogene 28, 1320–1328 (2009). https://doi.org/10.1038/onc.2008.475

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