TRPM8 as an Anti-Tumoral Target in Prostate Cancer Growth and Metastasis Dissemination

Int J Mol Sci. 2022 Jun 15;23(12):6672. doi: 10.3390/ijms23126672.

Abstract

In the fight against prostate cancer (PCa), TRPM8 is one of the most promising clinical targets. Indeed, several studies have highlighted that TRPM8 involvement is key in PCa progression because of its impact on cell proliferation, viability, and migration. However, data from the literature are somewhat contradictory regarding the precise role of TRPM8 in prostatic carcinogenesis and are mostly based on in vitro studies. The purpose of this study was to clarify the role played by TRPM8 in PCa progression. We used a prostate orthotopic xenograft mouse model to show that TRPM8 overexpression dramatically limited tumor growth and metastasis dissemination in vivo. Mechanistically, our in vitro data revealed that TRPM8 inhibited tumor growth by affecting the cell proliferation and clonogenic properties of PCa cells. Moreover, TRPM8 impacted metastatic dissemination mainly by impairing cytoskeleton dynamics and focal adhesion formation through the inhibition of the Cdc42, Rac1, ERK, and FAK pathways. Lastly, we proved the in vivo efficiency of a new tool based on lipid nanocapsules containing WS12 in limiting the TRPM8-positive cells' dissemination at metastatic sites. Our work strongly supports the protective role of TRPM8 on PCa progression, providing new insights into the potential application of TRPM8 as a therapeutic target in PCa treatment.

Keywords: ERK; FAK; Rho signaling; TRPM8; cell proliferation; invasion; metastasis dissemination; prostate cancer; trans–endothelial migration; tumor growth.

MeSH terms

  • Animals
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Humans
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Neoplasm Metastasis / pathology
  • Prostate / pathology
  • Prostatic Neoplasms* / metabolism
  • TRPM Cation Channels* / genetics
  • TRPM Cation Channels* / metabolism

Substances

  • Membrane Proteins
  • TRPM Cation Channels
  • TRPM8 channel-associated factor 1 protein, human
  • TRPM8 protein, human
  • TRPM8 protein, mouse