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TRPV6 Calcium Channel Translocates to the Plasma Membrane Via Orai1-Mediated Mechanism and Controls Cancer Cell Survival

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TRPV6 Calcium Channel Translocates to the Plasma Membrane Via Orai1-Mediated Mechanism and Controls Cancer Cell Survival TRPV6 calcium channel translocates to the plasma PNAS PLUS membrane via Orai1-mediated mechanism and controls cancer cell survival Maylis Raphaëla,1,V’yacheslav Lehen’kyia,1,2, Matthieu Vandenberghea,1,3, Benjamin Becka,4, Sergiy Khalimonchyka, Fabien Vanden Abeelea, Leonardo Farsettia, Emmanuelle Germaina, Alexandre Bokhobzaa, Adriana Mihalacheb, Pierre Gossetb, Christoph Romaninc, Philippe Clézardind, Roman Skrymaa, and Natalia Prevarskayaa,2,5 aInstitut National de la Santé et de la Recherche Médicale U1003, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Laboratory of Excellence Ion Channel Science and Therapeutics, Université des Sciences et Technologies de Lille, 59655 Villeneuve d’Ascq, France; bDepartment of Cell Pathology, Catholic Institute of Lille, University of Lille Nord de France, St. Vincent Hospital, 59020 Lille, France; cInstitute for Biophysics, Johannes Kepler Universität, A-4040 Linz, Austria; and dInstitut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1033, Faculty of Medicine Lyon-Est, 69372 Lyon Cedex 08, France Edited by Lutz Birnbaumer, National Institute of Environmental Health Sciences, Research Triangle Park, NC, and approved August 1, 2014 (received for review July 15, 2014) Transient receptor potential vanilloid subfamily member 6 (TRPV6) in cancer cells were shown to stimulate proliferation (12) or in- is a highly selective calcium channel that has been considered as duce migration (17), while sustained increase may prevent apo- a part of store-operated calcium entry (SOCE). Despite its first dis- ptosis (18). Because, on one hand, TRPV6 is overexpressed in + covery in the early 2000s, the role of this channel in prostate cancer PCa, and on the other hand, it controls Ca2 homeostasis in these (PCa) remained, until now, obscure. Here we show that TRPV6 cells, our studies were devoted to show the role and significance of + mediates calcium entry, which is highly increased in PCa due to the the TRPV6 channel in Ca2 signaling/remodeling in PCa, with remodeling mechanism involving the translocation of the TRPV6 a particular insight into molecular mechanisms of its implica- channel to the plasma membrane via the Orai1/TRPC1-mediated tion therein, its involvement in such calcium-dependent pro- 2+ Ca /Annexin I/S100A11 pathway, partially contributing to SOCE. cesses as cell survival and apoptosis resistance, and to confirm its CELL BIOLOGY The TRPV6 calcium channel is expressed de novo by the PCa cell role in PCa tumorigenesis in vivo. to increase its survival by enhancing proliferation and conferring apoptosis resistance. Xenografts in nude mice and bone metastasis Results models confirmed the remarkable aggressiveness of TRPV6-overex- The Expression of TRPV6 Protein Is Associated with the Cancer pressing tumors. Immunohistochemical analysis of these demon- Progression. Although the expression of the TRPV6 channel in strated the increased expression of clinical markers such as Ki-67, human tissues has already been reported using mRNA-specific prostate specific antigen, synaptophysin, CD31, and CD56, which are probes (7, 8) and antibodies (19), we intended to study its expres- strongly associated with a poor prognosis. Thus, the TRPV6 channel sion in human PCa samples using an antibody verified against acquires its oncogenic potential in PCa due to the remodeling mech- 2+ anism via the Orai1-mediated Ca /Annexin I/S100A11 pathway. Significance rostate cancer (PCa) develops as a slow cancer in the ma- Transient receptor potential vanilloid subfamily member 6 Pjority of cases and is still the second most lethal tumor among (TRPV6) is a highly selective Ca2+ channel that exercises its + men (1, 2). It belongs to the group of malignant tumors where normal physiological function via Ca2 absorption in the in- enhanced proliferation is accompanied by acquired resistance to testine and kidney. Intriguingly, we show that the TRPV6 apoptosis (3, 4). In addition, PCa cells become resistant to any channel may switch from its well-known constitutive activity anticancer treatment during PCa progression, acquiring more to the store operated due to the remodeling mechanism in- aggressive phenotype characterized by the enhanced cell survival volving STIM1/Orai1/TRPC1-induced activation of TRPV6 chan- and apoptosis resistance. Despite a growing number of studies, nel translocation to the plasma membrane via the Ca2+/ the mechanisms leading to these phenotypes are still poorly Annexin I/S100A11 pathway. Moreover, we demonstrate that defined. An understanding of the factors that drive the evolution the discovered mechanism is used by prostate cancer cells. This of PCa is vital for the development of new therapies and new channel is absent in healthy prostate and is expressed de novo markers for advanced PCa. in prostate cancer cells, where it changes the role by supplying One such target has already been suggested. Transient receptor Ca2+, which is used in cancer to increase cell survival. potential vanilloid subfamily member 6 (TRPV6) is a highly se- lective calcium channel (5). Intriguingly, it is absent in the healthy Author contributions: M.R., V.L., F.V.A., and N.P. designed research; V.L., P.G., C.R., P.C., and R.S. contributed new reagents/analytic tools; M.R., V.L., M.V., B.B., S.K., F.V.A., L.F., prostate and becomes expressed in prostate adenocarcinoma, and E.G., A.B., and A.M. performed research; M.R., V.L., M.V., B.B., S.K., F.V.A., L.F., E.G., A.M., TRPV6 mRNA levels were shown to significantly correlate with P.G., C.R., P.C., and R.S. analyzed data; and V.L. and N.P. wrote the paper. the Gleason grading and are abundantly expressed in lymph node The authors declare no conflict of interest. metastasis of prostate origin (6, 7). Although, in the beginning of This article is a PNAS Direct Submission. the 2000s, TRPV6 was suggested as a prognostic marker to treat 1M.R., V.L., and M.V. contributed equally to this work. advanced prostate cancer (8), nothing is known thus far regarding 2V.L. and N.P. contributed equally to this work. the molecular mechanisms in which it is involved or the reason why 3Present address: Department of Medicine, Dermatology Research, University of Califor- PCa cells express the TRPV6 channel: does it have an oncogenic nia, San Diego, La Jolla, CA 92121. potential or play a role as a tumor suppressor? 4Present address: Institut de Recherche Interdisciplinaire en Biologie Humaine et Molécu- The role of calcium in global cancer-related cell signaling laire, Université Libre de Bruxelles, 1070 Bruxelles, Belgium. 2+ pathways is uncontested (9, 10). Alterations in Ca homeostasis 5To whom correspondence should be addressed. Email: [email protected]. in PCa are known to increase proliferation (11, 12) and induce This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 2+ differentiation (13) and apoptosis (14–16). Indeed, Ca transients 1073/pnas.1413409111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1413409111 PNAS Early Edition | 1of10 Downloaded by guest on September 30, 2021 heterologously expressed TRPV6-YFP chimera following anti-GFP lymph node cancer of the prostate (LNCaP) cells, silencing of antibody, as well as in confocal imaging using pIRES-TRPV6 either Stim1 or Orai1, which is now considered as the hard core of nucleofected HEK293 cells (Fig. S1 A and B). Our data show that SOCs, inhibited TG-evoked ISOC by 80% (Fig. 2 A and B; n = 15 TRPV6 may be very slightly expressed in benign prostate hyper- per condition). The same data were obtained using inositol-1,4,5- plasia (BHP), and its expression increases in carcinomatous pros- triphosphate (InsP3)-evoked ISOC (Fig. S1 G and H). Down-reg- tates (Fig. 1). Its expression is heterogeneous and is found at the ulation of TRPC1 and TRPV6 also decreased ISOC magnitude, apex of certain epithelial cancer cells in samples of adenocarci- suggesting a composition of endogenous SOC wider than Stim1/ nomas (ADCs) having a Gleason score of 7. The Orai1 channel Orai1. Indeed, siRNA against TRPV6 decreased SOC magnitude by 50% (45 ± 9.6%; n = 14; Fig. 2 A and B). This result was is mostly expressed in basal cells in the normal prostate and is + subject to relocalization in apex/intra luminal cells in BHP and confirmed by FURA-2 Ca2 imaging experiment where STIM1 cancer. STIM1 and TRPC1 are homogeneously expressed in was used as a positive control (Fig. 2C), showing that in cells prostate epithelial and cancer cells. The sections from the same down-expressing TRPV6, SOCE magnitude is two times lower patients were also stained for Ki-67, caspase-3–cleaved frag- than in control conditions (Fig. 2D). To know whether the TRPV6 ment, and prostate specific antigen (PSA). Like the TRPV6 channel is transactivated by STIM1, we studied its coimmuno- channel, Ki-67 staining was also elevated in ADCs having precipitation with STIM1 under store depletion using 1 μMTG. a Gleason score of 7, and the caspase-3–cleaved fragment is STIM1 failed to precipitate the TRPV6 channel (Fig. 1E)andvice almost absent in apical epithelial cells from the same patients versa (Fig. 2F), whereas STIM1 did precipitate Orai1 and vice versa (Fig. S1C). Antibody against PSA showed uniform staining of (as it did for TRPC1; Fig. S2 I and J), which has already been benign or malignant epithelial cells. Thus, TRPV6 expression reported (22) and is used as a control in these studies (Fig. 2 G and correlates with the Gleason score, Orai1, TRPC1, PSA, and the H). Surprisingly, coimmunoprecipitation of the TRPV6 channel K expression of the proliferation marker Ki-67. yielded TRPC1 bands (Fig. S2 ). Moreover, although the TRPC1 channel was precipitated, we revealed TRPV6-specific bands (Fig. TRPV6 Channel Translocation to the Plasma Membrane Is Regulated S2L), suggesting a possible interaction between TRPC1 and TRPV6 via Ca2+/Annexin I/S100A11 Signaling Independent of STIM1.
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