Targeting of short TRPM8 isoforms induces 4TM-TRPM8-dependent apoptosis in prostate cancer cells
Gabriel Bidaux1,2,3, Anne-Sophie Borowiec1,2, Charlotte Dubois1,2
1Inserm, U-1003, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villeneuve d'Ascq, France.
Abstract:
Since its cloning a decade ago, TRPM8 channel has emerged as a promising prognostic marker and a putative therapeutic target in prostate cancer (PCa). However, recent studies have brought to light the complexity of TRPM8 isoforms in PCa. Consequently, the respective role of each TRPM8 isoform needs to be deciphered prior to considering TRPM8 as an attractive therapeutic target. Full-length (6 transmembrane (TM)-domain) TRPM8 channel is overexpressed in early PCa and repressed in advanced prostate tumors whereas the localization of the truncated, 4TM-TRPM8 channel (4 transmembrane (TM)-domain), in the membranes of endoplasmic reticulum (ER) is independent of the pathogenic status of epithelial cells. In the same line, expression of non-channel cytoplasmic small TRPM8 isoforms (namely sM8) is conserved in cancer cells. In this study, we identify sM8s as putative regulator of PCa cell death. Indeed, suppression of sM8 isoforms was found to induce concomitantly ER stress, oxidative stress, p21 expression and apoptosis in human epithelial prostate cancer cells. We furthermore demonstrate that induction of such mechanisms required the activity of 4TM-TRPM8 channels at the ER-mitochondria junction. Our study thus suggests that targeting sM8 could be an appropriate strategy to fight prostate cancer.
Insights
Targeting small TRPM8 (sM8) isoforms may fight prostate cancer (PCa). Suppressing sM8 induces ER stress, oxidative stress, and apoptosis, requiring 4TM-TRPM8 channel activity at the ER-mitochondria junction.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- TRPM8 channel is a prognostic marker and therapeutic target in prostate cancer (PCa).
- Different TRPM8 isoforms (full-length, 4TM-TRPM8, sM8) exhibit varied roles and localizations in PCa progression.
- The specific functions of TRPM8 isoforms in PCa pathogenesis require further elucidation.
Purpose of the Study:
- To investigate the role of small TRPM8 (sM8) isoforms in prostate cancer cell death.
- To determine the mechanisms by which sM8 influences PCa cell fate.
- To evaluate the potential of targeting sM8 as a therapeutic strategy for PCa.
Main Methods:
- Studied the effects of sM8 suppression in human epithelial prostate cancer cells.
- Assessed ER stress, oxidative stress, p21 expression, and apoptosis.
- Investigated the role of 4TM-TRPM8 channels at the ER-mitochondria junction.
Main Results:
- Suppression of sM8 isoforms induced ER stress, oxidative stress, p21 expression, and apoptosis.
- The observed effects were dependent on the activity of 4TM-TRPM8 channels.
- 4TM-TRPM8 channel activity was crucial at the ER-mitochondria junction for inducing cell death mechanisms.
Conclusions:
- sM8 isoforms act as regulators of prostate cancer cell death.
- Targeting sM8 isoforms represents a potential therapeutic strategy for prostate cancer.
- The interplay between sM8, 4TM-TRPM8 channels, and ER-mitochondria suggests novel therapeutic avenues.
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