TRPV6 In Prostate Cancer: What is the significance?


The transient receptor potential proteins (TRPs) are a family of ion channels involved in different cellular functions. TRP channels are ubiquitously distributed throughout the mammalian system. And based on their sequence homology they have been divided into six families: TRPC, TRPV, TRPM, TRPN, TRPA, and TRPP. TRP subunits assemble as homo- or hetero-tetramers to form cation selective channels which are activated by a wide range of stimuli including intra- and extracellular messengers, chemical, mechanical and osmotic stress, temperature, growth factors and by the depletion of intracellular calcium stores.

TRPV6 channel cDNA was cloned in 1999 from rat duodenum by expression cloning using Xenopus oocytes (Peng et al. 1999). Like other TRP family members it is necessary for a wide variety of physiological functions. TRPV6 expression is mainly confined to epithelial tissue of different organs such as digestive tract, kidney, testis, ovaries and skin. TRPV6 has a high calcium selectivity and is involved in the regulation of calcium homeostasis in the body. Published data have demonstrated its upregulation in cancer and correlation with the advanced stages in prostate cancer (stage pT2a and pT2b). However its role in the initiation or progression of most cancers is not yet understood. The in vitro oncogenicity of TRPV6 in prostate cancer has been proposed to operate via calcium signalling control of processes such as proliferation and resistance to apoptosis (Prevarskaya et. al., 2007)

Many publications over the years have demonstrated a correlation between TRV6 expression in prostate tissue and prostate cancer. Lehen (2007) have shown that Ca2+ entry via TRPV6 controlled proliferation directly and promoted apoptotic resistance in prostate cancer cells and concluded that the upregulation of TRPV6 may represent a mechanism for maintaining a higher proliferation rate. In view of the strong correlation between TRPV6 expression levels with the Gleason score >7 tumor grading, the channel represents a promising new therapeutic target prostate cancer treatment.

Conversely, other studies have shown that in healthy and benign human prostate tissue the expression levels of TRPV6 mRNA are very low if not undetectable. In 2012 Raphael et al used in situ hybridization methods to demonstrate that TRPV6 mRNA transcripts were undetectable in high-grade prostatic neoplasia and incidental adenocarcinoma but were increased in prostate adenocarcinoma (1B). Additionally, work by Wissenbach et al., (2004) on biopsies of prostate cancer tissue has shown that TRPV6 mRNA expression increases with the degree of aggressiveness of the cancer (1A), as assessed by the Gleason score and the degree of metastasic spread. Both studies suggest that expression levels of TRPV6 could be an excellent marker to predict the clinical outcome of prostate cancer.

Figure 1: Expression of TRPV6 in prostate cancer.

1A                                         1B

 

Figure 1 A. Northern blot analysis using cDNA probes of human TRPV6, TRPM4 and TRPM8 cDNA. (Ref). Both TRPm4 and TRPV6 transcripts are detectable in prostate cancer but not in benign prostate tissue (Biochemical and biophysical Research communication 322 (2004) 1359-1363).

Figure 1B. Immuno-histochemical staining of human prostate tissue using Anti-TRPV6 antibody. Very low expression of TRPV6 is observed in normal and benign hyperplasia (BHP) as opposed to significant expression in prostate adenocarcinoma (ADC 7). Adapted from Raphael, M. et al. (2014) Proc. Natl. Acad. Sci. U.S.A. 111, E3870.

In summary, the specific expression pattern in prostate cancer coupled with its physiological function as a calcium selective channel suggests that TRPV6 may be a promising drug discovery target for the possible treatment of prostate cancer.

 Blog written by H I Choudhury (Shamim)

References:

  • Maylis Raphael¨ et. al. (2012); Role of the TRPV6 channel in cancer. J Physiol 590.6 pp 1369–1376 1369
  • V Lehen’Kyi et al., (2007) TRPV6 channel controls prostate cancer cell proliferation via Ca2+/NFAT-dependent pathways Oncogene 26, 7380–7385
  • Wissenbach et al., (2004) TRPV6 and prostate cancer: growth beyond the prostate correlates with increase TRPv6 Ca+ channel expression. Biochemical and biophysical Research communication 322, 1359-1363
  • Thomas Fixemer et al., (2003) Expression of the Ca2þ-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression. Oncogene (2003) 22, 7858–7861
  • Natalia Prevarskaya et. al., (2007) TRP channels in cancer Biophysica Acta 1772, 937–946

 

 

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