Loss of TRPV2 Homeostatic Control of Cell Proliferation Drives Tumor Progression

Abstract

Herein we evaluate the involvement of the TRPV2 channel, belonging to the Transient Receptor Potential Vanilloid channel family (TRPVs), in development and progression of different tumor types. In normal cells, the activation of TRPV2 channels by growth factors, hormones, and endocannabinoids induces a translocation of the receptor from the endosomal compartment to the plasma membrane, which results in abrogation of cell proliferation and induction of cell death. Consequently, loss or inactivation of TRPV2 signaling (e.g., glioblastomas), induces unchecked proliferation, resistance to apoptotic signals and increased resistance to CD95-induced apoptotic cell death. On the other hand, in prostate cancer cells, Ca2+-dependent activation of TRPV2 induced by lysophospholipids increases the invasion of tumor cells. In addition, the progression of prostate cancer to the castration-resistant phenotype is characterized by de novo TRPV2 expression, with higher TRPV2 transcript levels in patients with metastatic cancer. Finally, TRPV2 functional expression in tumor cells can also depend on the presence of alternative splice variants of TRPV2 mRNA that act as dominant-negative mutant of wild-type TRPV2 channels, by inhibiting its trafficking and translocation to the plasma membrane. In conclusion, as TRP channels are altered in human cancers, and their blockage impair tumor progression, they appear to be a very promising targets for early diagnosis and chemotherapy.

Figure 1

TRPV2 protein expression during GSC differentiation. (A) TRPV2 protein expression in undifferentiated and differentiated GSCs was evaluated by immunocytochemistry analysis. GSCs were incubated with goat anti-TRPV2 antibody followed by the respective secondary antibody. The detection was performed by avidin-biotin complex peroxidase method and diaminobenzidine (DAB) as a chromogen. The result shown that a moderate reaction that stains all the cytoplasm occurs in differentiated GSCs compared to the undifferentiated GSCs. (B) Membrane and cytoplasm fractions from undifferentiated or differentiated GSCs were immunoblotted with anti-TRPV2 antibody. Total lysates were also immunoblotted with anti-GFAP, anti-βIII-tubulin and anti-nestin antibodies. GAPDH protein was used as loading control.

Figure 2

s-TRPV2 expression in human normal urothelial and urothelial carcinoma cell lines. cDNA from NHUCs and RT4, EJ, and J82 cell lines was amplified by PCR for TRPV2 expression. PCR products were analyzed by electrophoresis on 2% ethidium bromide-stained agarose gel. The hTRPV2-plasmid construct was used as positive control (+). Arrows indicate the two products obtained. MW = molecular weight.