TRPV6 channels and Cancer
Introduction to TRPV6 channels
Calcium ion is a major signaling component in many cell processes and so its concentration is very closely regulated in cellular compartments. In 1999 a novel calcium channel was reported in rabbit kidney tubules (ECaC; Hoenderop et al. 1999) which was quickly followed by identification of a related channel in rat gut (CaT1; Peng et al., 1999). These channels bore sequence resemblance to the capsaicin receptor (VR1: vanilloid receptor) reported earlier (Caterina et al., 1997).
ECaC1 and CaT1 (now TRPV5 and TRPV6, respectively), and VR1 (now TRPV1) were recognized as being related to transient receptor potential calcium channels (TRP channels) from Drosophila eye where they mediate photoreception (Montell, 2003). To date, mammals are reported to have 28 genes for TRP channels divided into six families: TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin) and TRPV (vanilloid) (Pederson et al., 2005; Gees et al. 2010; Nilius and Szallasi 2014). These channels are also distinguished from those calcium channels in excitable tissues (e.g. nerve, neuron) in that they are not formally voltage-gated.
A sub-family of TRP channels that has received a great deal of study is the TRPV group. Six members, TRPV1 to TRPV6, comprise this group. The first four of the channels are more closely related and have functions in sensing heat, acid, stretching/osmotic strain, nociception and pain signal integration (reviewed in Li et al. 2011). TRPV5 and TRPV6, while clearly related to the first four cousins, have significantly different properties. TRPV5 and TRPV6 are more selective for calcium ion (e.g. PCa/PNa ~ 100) compared to the other four (1 to ~15) and are constitutively active. A major function of these two channels appears to be calcium homeostasis. TRPV5 is expressed predominantly in the distal tubules of the kidney where it reclaims calcium from the pre-urine stream (Nijenhuis et al., 2003). TRPV6, while produced in kidney tubules at lower levels than TRPV5, is predominant in the intestine where it has a role in calcium import.
TRPV6 and Cancer
While recent studies with TRPV6 knock-out mice indicate and reinforce the involvement of this channel in calcium homeostasis (Bianco, 2007), over-expression of the channel has been reported in human malignancies. An early report indicated large amounts of TRPV6 mRNA were measured in a colorectal cancer cell line (SW480) and a chronic myelogenous leukemia cell line (K-562) (Peng et al., 2000). Wissenbach et al. (2001) reported up-regulation of TRPV6 mRNA in prostate cancer while Peng et al. (2001) reported significant elevation of the messenger in prostate cancer cell lines LNCaP and PC3. Most strikingly, Peng et al. (2001) reported a positive correlation of the TRPV6 mRNA signal with the Gleeson scoring of prostate tumours. A recent publication (Peters et al. 2012) confirms TRPV6 as a therapeutic target in estrogen receptor negative breast cancers and shows that up-regulated production of the channel is important in progression of the disease.
An immunohistochemical approach to determine the amounts of TRPV6 in healthy and malignant tissues confirmed the early work showing small amounts of protein in normal exocrine tissues (e.g. mammary gland, pancreas, prostate) but greatly elevated amounts in carcinomas of breast, colon, ovary, prostate and thyroid (Zhuang et al., 2002). Fixemer et al. (2003) expanded and confirmed the positive correlations between TRPV6 over-expression and Gleason scores, pathological stage and extra-prostatic extensions. TRPV6 channel increases were reported in rat leukemia cells (Bodding et al., 2002) and the human leukemia cell line, K562 (Semenova et al., 2009). The predictive role of TRPV6 in prostate malignancies was suggested by the interpretation that TRPV6-positive tumours have poor prognosis because of a propensity to invade extra-prostate tissues (Wissenbach et al., 2004). The exact role of TRPV6 in cancer proliferation is not clear, but the calcium-dependent proliferation of cancer cells was linked directly to the channel (Schwarz et al., 2006). The role of TRP channels in cancer has been reviewed (Prevarskaya et al., 2007; Bodding, 2007; Nilius et al., 2007; Santoni et al., 2011; Fecher-Trost et al. 2014) while a general role of the TRP channels in prostate gland have recently been reviewed (van Haute, 2010).
It now appears that the influence of elevated TRPV6 in cancers includes downstream activation of the nuclear factor of activated T-cell (NFAT) transcription factors in cell lines of prostate (Lehen’kyi et al., 2007) and breast cancer (Bolanz et al., 2008). In the two latter studies reduction of TRPV6 expression with silencing RNA reduced proliferation and increased apoptosis in these cell lines. SBI has also examined the activation of one of the five NFAT isoforms in ovarian, breast and prostate cancer cell lines, in ovarian tumour biopsies and in xenograft tumours produced from an ovarian cancer cell line (SKOV-3) and breast cancer cell line (T 47D), and have observed activation of NFATc1 (dephosphorylation by Ca-calmodulin-activated calcineurin). Such activation requires sustained rather than spiking increases in internal Ca+² concentration. There is a growing consensus that this pathway is involved in both increased cell proliferation and inhibition of apoptosis that is reflected in a recent review article (Figure 2, Huber, 2013).
Working Model of Mechanism of Action
TRPV6 and Cancer: Selected Bibliography
Below is a selection of significant publications showing the link between over-expression of the TRPV6 ion channel and oncology. The active links will provide either a pdf download from an open access site or access to the PubMed citation.
, M. et al. 2002. The recombinant human TRPV6 channel functions as Ca2+ sensor in human embryonic kidney and rat basophilic leukemia cells. J. Biol. Chem. 277(39): 36656—36664. http://www.jbc.org/content/277/39/36656.long
Fecher-Trost, C. et al. 2014. TRPV6 channels. Handb Exp Pharmacol 222:359 – 384. http://www.ncbi.nlm.nih.gov/pubmed/24756713
, T. et al. 2003. Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression. Oncogene, 22(49): 7858—7861. http://www.ncbi.nlm.nih.gov/pubmed/14586412
Nilius, B. and Szallasi, A. 2014. Transient receptor potential channels as drug targets from the science of basic research to the art of medicine. Pharmacol Rev 66(3): 676 – 814.
Peleg, S. et al. 2010. Suppression of aberrant transient receptor potential cation channel, subfamily V, member 6 expression in hyperproliferative colonic crypts by dietary calcium. Am J Phyisol Gastrointest Liver Physiol 299: G593 – G601. http://ajpgi.physiology.org/content/299/3/G593
Peters, A. A., et al. 2012. Calcium channel TRPV6 as a potential therapeutic target in estrogen receptor negative breast cancer. Molecular Cancer Therapy. Published online, 17 July, 2012.
, G. et al. 2011. TRPV Channels in Tumor Growth and Progression, in Ed. M. S. Islam, Transient Receptor Potential Channels, Ch 49. Adv. in Exp. Med. Biol. 704, DOI 10.1007/978-94-007-0265-3_49. Springer+Business Media B. V. 2011. http://www.ncbi.nlm.nih.gov/pubmed/21290335
, U. 2004. TRPV6 and prostate cancer: cancer growth beyond the prostate correlates with increased TRPV6 Ca2+ channel expression. Biochem. Biophys. Res. Comm. 322: 1359—1363. http://www.ncbi.nlm.nih.gov/pubmed/15336984
, L. et al. 2002. Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies. Lab Invest. 82(12): 1755—1764. http://www.ncbi.nlm.nih.gov/pubmed/12480925