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PSA reduces prostate cancer cell motility by stimulating TRPM8 activity and plasma membrane expression
D Gkika1, M Flourakis, L Lemonnier
1Inserm, U1003, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, France.
Abstract:
Although the transient receptor potential melastatin 8 (TRPM8) cold receptor is highly expressed in prostate cancer (PCa) and constitutes a promising diagnostic and prognostic indicator, the natural agonists of this channel in the prostate, as well as its physiological and pathological functions, remain unknown. In this study, we identified the well-known PCa marker, prostate-specific antigen (PSA), as a physiological TRPM8 agonist. Electrophysiological and Ca(2+) imaging studies demonstrated that PSA activated TRPM8-mediated current by the bradykinin 2 receptor signaling pathway. Further investigation of this mechanism by cell-surface biotinylation revealed that the increase in TRPM8 current induced by PSA was due to an increase in the number of functional TRPM8 channels on the plasma membrane. Importantly, wound-healing and migration assays revealed that TRPM8 activation by PSA reduced motility of the PC3 PCa cell line, suggesting that plasma membrane TRPM8 has a protective role in PCa progression. Consequently, PSA was identified as a natural TRPM8 agonist in the prostate and we propose a putative physiological role for both of these proteins in carcinogenesis, making this pathway a potentially important target for anticancer agent development.
Insights
Prostate-specific antigen (PSA) activates the TRPM8 cold receptor in prostate cancer cells, reducing cancer cell motility. This discovery reveals a natural TRPM8 agonist and suggests a protective role for TRPM8 in cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Physiology
Background:
- Transient receptor potential melastatin 8 (TRPM8) is highly expressed in prostate cancer (PCa).
- The natural agonists and physiological functions of TRPM8 in the prostate are currently unknown.
- TRPM8 is a potential diagnostic and prognostic indicator for PCa.
Purpose of the Study:
- To identify natural agonists of TRPM8 in the prostate.
- To elucidate the physiological and pathological functions of TRPM8 in PCa.
- To investigate the role of TRPM8 in PCa progression.
Main Methods:
- Electrophysiology and Ca(2+) imaging to study TRPM8 activation.
- Cell-surface biotinylation to assess TRPM8 channel trafficking.
- Wound-healing and migration assays to evaluate cell motility.
Main Results:
- Prostate-specific antigen (PSA) was identified as a physiological TRPM8 agonist.
- PSA activates TRPM8 via the bradykinin 2 receptor signaling pathway.
- PSA increases the number of functional TRPM8 channels on the plasma membrane.
- TRPM8 activation by PSA reduces PC3 PCa cell line motility.
Conclusions:
- PSA is a natural TRPM8 agonist in the prostate.
- Plasma membrane TRPM8 plays a protective role in PCa progression by reducing cell motility.
- The PSA-TRPM8 pathway represents a potential therapeutic target for anticancer agent development.
