We know cancerous cells have a different mechanism and calcium signalling is the most important pathway in cancer. But the little bit we know that TRPV6  family which is a group of protein also play a vital role in cancer signalling. From the normal cell to a cancer cell formation involves a mutation in key signalling protein and it is encoded by tumour suppressor genes or oncogenes. In this article, we will investigate the role of TRPV6 in cancer.

Trp family is included in oncogenic and tumour suppressor protein. We will discuss how Trp 6 which is a member of the Trp family protein lead to cancer formation.

Certain Trpv1 family has an antioncogenic property which is essential for the stopping of cancer.

 TRPV6

Trpv6 is a calcium-mediated membrane protein that is involved in the formation of cancer. It is also involved in calcium absorption in the intestine. Also known as calcium transport protein 1. Trpv6 means transient receptor potential vanilloid subfamily member 6 belongs to the transient receptor potential family.

Trp family group of channel protein which detects temperature, osmotic pressure taste and mechanical forces. Human has 8 Trp channels, which include 6 families of Trpv. Trpv5 and Trpv6 have high calcium selectivity while others are involved in heat sensors and or sensing osmolarity.

Role Of TRPV6 In Cancer

Role of TRPV6 in cancer

Epithelial integrity disrupts when TRPV6 is lost from mammary epithelial cells. Furthermore, the expression level of TRPV6 was tightly linked to the levels of common EMT markers, suggesting that TRPV6 may have a role in the mesenchymal invasion of breast cancer cells.

Thus, the TRPV6 level if too high or too low it compromise the homeostasis of the mammary epithelial sheets and progression of the pathophysiological condition. It plays a very important role in cancer treatment as it increases the intracellular calcium and initiates the downstream pathway that leads to cell proliferation and inhibition of apoptosis.

As we know calcium is the main key in cancer proliferation. Elevated calcium in cancer leads to metastasis. Upregulation of these Trpv6 has been seen in prostate cancer. The exact role of Trpv6 in cancer is not clear but calcium dependant proliferation of cancer cells was linked directly to Trpv6. The over-expression of TRPV6 mRNA and protein is reported in many cancer.

TRPV6 is classified as an oncochannel and genes are known as oncogene whereas there is no evidence that high expression of these TRPV6 can induce cancer. Trpv6 amount was high in breast, thyroid and ovary cancer. Trpv6 role in cancer proliferation is not clear, but cancer cell which occurs due to high proliferation of calcium was linked to Trpv6.

Increased TRPV6 mRNA is reported in breast cancer and a greater amount of trpv6 is present in breast cancer as compared to normal cells.

Trpv6 was present in low levels in the tissue-like pancreas and mammary gland.

Reducing TRPV6 production with siRNA in breast, and prostate cancer cell lines resulted in decreased cell proliferation and increased apoptosis.

Mechanism of Trpv6 as an oncogene

Elevated Trpv6 and subsequent increase in cytosolic calcium activate the nuclear factor (NFAT). Overexpression of Trpv6 cause increased calcium. Activated nfat translocates to the nucleus and activate membrane type 1 matrix and autotaxin. It is also believed that the apoptotic nature of Trpv6 comes from increased production of BCL-2, which prevent apoptosome formation.

Vitamin D and Trpv6

 TRPV6 ion channel production is activated by vitamin D3. Vitamin receptors (VDR)  have vitamin D which bind to the TRPV6  gene element which activates transcription.

 It is an obligate heterodimer with retinoic acid receptor alpha in its active form.

GADD45 α  is activated by the transcription of Vitamin D which is produced in responses to DNA damage or growth stressed conditions. 

GADD45α activates MEKK4 (Mitogen-Activated Protein kinase kinase kinase) that in turn activates p38α and JNK.

JNK activates as NFAT4 and NFATc2   allow for apoptotic activity.

Conclusion

 TRPV6 is a major target to disrupt calcium homeostasis and to stop cancer formation. Reduction of TRPV6 activity by decreasing expression of the channel has shown efficacy in four cancer types: adenocarcinomas of breast, ovarian, prostate and pancreas, TRPV6 gene expression is unclear and protein production is up-regulated in cancer and this kind of cancer may exploit TRPV6  gene.

 Disrupting the Trpv6 channel in cancer can stop the calcium and lead to the killing of cancer cells.

References

https://www.meta.org/papers/Trpv6-as-a-target-for-cancer-therapy/31897233

https://www.nature.com/articles/s41598-020-71645-z

https://www.ncbi.nlm.nih.gov/books/NBK92828/

https://www.sciencedirect.com/science/article/pii/S0925443907001135

https://www.hindawi.com/journals/isrn/2012/458238/

https://www.nature.com/articles/s41419-019-1708-9

https://www.sciencedirect.com/science/article/pii/S0167488908004102