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TRPV6 - Mechanism of Action in Cancer Promotion

TRPV6, a member of one of seven subfamilies of TRP channels, is a non-voltage-gated, non-receptor-operated calcium-specific ion channel. In a healthy state, it plays an important role in calcium absorption from the gut. In an unhealthy state, TRPV6 plays a key role in cancer pathogenesis including cancer cell growth, proliferation, metastasis and resistance to programmed death.

Although the precise details of the TRPV6 pathway in cancer remain to be fully elucidated, a viable model now exists and is based on increased intracellular calcium resulting from the over-expression of TRPV6.

TRPV6 plays a key role in cancer pathogenesis

MOA at the Gene and Protein Level

Bolanz, K.A., M.A. Hediger, and C.P. Landowski. Mol Cancer Ther, 2008. 7(2): p. 271-9.
Lehen'kyi, V., et al. Oncogene, 2007. 26(52): p. 7380-5

An increase in TRPV6 expression in the membrane of normal cells activates precancerous pathways by facilitating calcium influx into the cell (1). These calcium ions bind to the calcium binding protein calmodulin (CaM).  This complex activates calcineurin (Calnr): a CaM/Ca2+ activated phosphatase that de-phosphorylates and activates Nuclear Factor of Activated T-cells (NFAT), a gene transcription factor (2).  Active NFAT moves to the nucleus of the cell where, with Jun/Fos (two auxiliary transcription proteins from “cancer causing genes”), activates a number of intracellular pro-cancerous agents (3) including:

  1. Matrix Metalloproteinases (MT1-MMP and MMP2) – these enzymes play a pivotal role in tumor growth and the multistep processes of cancer invasion and metastasis.
  2. Autotaxin - an extracellular phospholipase that activates Growth Factor Receptor (GFR). Growth factor receptors are the first stop in cells where the signaling cascade for cell differentiation and proliferation begins.
  3. Bcl-2 and BclX – proteins which block the normal cellular process of programmed cell death (apoptosis). This resistance to apoptosis gives cancer cells the ability to remain “immortal” – that is, live forever.

Based on the key role that TRPV6 plays in the activation of this pro-cancerous pathway, any inhibition of this calcium channel would be expected to profoundly reduce the cancer cell’s ability to grow, proliferate, metastasize and would make the cell less resistant to apoptotic mechanisms. Over expression of TRPV6 might also be a protective mechanism deployed by cancer cells to avoid apoptotic cell death. Learn how Soricimed is developing new cancer treatments that target and inhibit TRPV6.

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