Antioncogenic effects of transient receptor potential vanilloid 1 in the progression of transitional urothelial cancer of human bladder.

The progression of normal cells to a tumorigenic and metastatic state involves the accumulation of mutations in multiple key signaling proteins, encoded by oncogenes and tumor suppressor genes. Recently, members of the TRP channel family have been included in the oncogenic and tumor suppressor protein family. TRPM1, TRPM8, and TRPV6 are considered to be tumor suppressors and oncogenes in localized melanoma and prostate cancer, respectively. Herein, we focus our attention on the antioncogenic properties of TRPV1. Changes in TRPV1 expression occur during the development of transitional cell carcinoma (TCC) of human bladder. A progressive decrease in TRPV1 expression as the TCC stage increases triggers the development of a more aggressive gene phenotype and invasiveness. Finally, downregulation of TRPV1 represents a negative prognostic factor in TCC patients. The knowledge of the mechanism controlling TRPV1 expression might improve the diagnosis and new therapeutic strategies in bladder cancer. 1. Part 1 1.1. TRPV1: Structure and Function. The TRPV1 channel is predicted to have six transmembrane domains and a short, pore-forming hydrophobic stretch between the fifth and sixth transmembrane domains. It is activated by capsaicin [1], noxious heat (>43◦C), low pH (5.2) [1–3], voltage [4, 5], various lipids [2, 6–11], and other pungent compounds such as zingerone, piperine, and those found in garlic and onion, such as allicin [12]. Similar to other sixtransmembrane domain channels, TRPV1 probably forms a tetrameric quaternary structure [13], where each subunit contributes to the ion-conducting pore and the selectivity filter. Although all known TRP channels are cation selective, their permeability for different monovalent and divalent cations varies among their subtypes [14–16]. Ion permeation is controlled by allosteric interactions among the subunits and by an activation gate which, as for voltage-gated potassium channels, is most probably located in the innermost region of the S6 segment [17, 18]. In this regard TRPV1 channels also exhibit voltage-dependent behaviour [19]. Splice variants of the TRPV1 channel have been reported in several species. For example, the human TRPV1b splice variant, which lacks exon 7 corresponding to 60 aminoacids in the N-terminal region of the channel, can be found in DRG neurons and in the CNS [20]. It was first reported that TRPV1b could be activated by heat, but not by capsaicin or low pH [21]. However, in a more recent study it was demonstrated that this splice variant is unresponsive to vanilloid agonists, heat, and protons and can inhibit channel function by associating with canonical TRPV1, functioning as a dominant-negative variant, thus suggesting that it constitutes an endogenous TRPV1 modulator.