The voltage-gated sodium channel Na_v1.7 associated with endometrial cancer

Abstract

Background: Endometrial cancer is the most common gynecologic malignancy in women in the developed countries. Despite recent progress in functional characterization of voltage-gated sodium channel (Na v) in multiple cancers, very little was known about the expression of Na v in human endometrial cancer. The present study sought to determine the role of Na v and molecular nature of this channel in the endometrial cancer. Methods: PCR approach was introduced to determine expression level of Na v subunits in endometrial cancer specimens. Pharmacological agents were used to investigate Na v function in endometrial cancer cells. Flow cytometry were used to test cancer apoptosis, and invasion assays were applied to test tumor metastasis. Results: Transcriptional levels of the all Na v α and β subunits were determined by real time-PCR in endometrial cancer with pair tissues of carcinoma and adjacent nonneoplastic tissue, Na v 1.7 was the most highly expressed Na v subtype in endometrial cancer tissues. Na v 1.7 level was closely associated with tumor size, local lymph node metastasis, and 5-year and 10-year survival ratio. Inhibition of this channel by Na v 1.7 blocker PF-05089771, promoted cancer apoptosis and attenuated cancer cell invasion. Conclusion: These results establish a relationship between voltage-gated sodium channel protein and endometrial cancer, and suggest that Na v 1.7 is a potential prognostic biomarker and could serve as a novel therapeutic target for endometrial cancer.

Pharmacological and nutritional targeting of voltage-gated sodium channels in the treatment of cancers

“…The activity of the channels at the plasma membrane appears to be critical. Indeed, Nava subunits are functionally active in cancer cell lines and primary tumor cells cultured in vitro, as well as in murine tumor xenograft tissue slices in vivo (Fraser et al, 2005;Roger et al, 2003;Hernandez-Plata et al, 2012;Nelson et al, 2015b), and their inhibition, using different drugs and small molecules such as TTX, ranolazine, phenytoin, Cn2 or PF-05089771, inhibits invasion (Nelson et al, 2015a(Nelson et al, , 2015bDriffort et al, 2014;Batcioglu et al, 2012;Yildirim et al, 2012;Lopez-Charcas et al, 2018;Roger et al, 2003Roger et al, , 2007Liu et al, 2019).…”

“…Na V 1.7 expression level was associated with tumor size, local lymph node metastasis, and 5-and 10-year survival. Pharmacological inhibition using the PF-05089771 blocker selective for Na V 1.7 and Na V 1.8 induced cancer cell apoptosis and reduced cancer cell invasion (Liu et al, 2019).…”

The Expression of Sodium Channel Alpha Subunit (Nav1.7) Receptors in Intracranial Meningioma and Its Comparison to Urothelial, Prostate and Ovarian Cancers

“…Nav1.7 has been found to be associated with endometrial carcinoma and suggested as a prognostic marker in a study published in 2019 (21). In a study on rat prostate cancer cell lines Mat-Lylu, suggested a role of Nav1.7 dependent regulation of Rho-GTPase activity in cell migration and invasion during carcinogenesis (22).…”

Exploring the Therapeutic Potential of Membrane Transport Proteins: Focus on Cancer and Chemoresistance

“…Similarly, upregulated Na V 1.6 was observed in primary cervical cancer cells, and its blockade inhibited invasion of those cells [263]. Furthermore, elevated expression of Na V 1.7 induces growth and invasion of prostate [264], gastric [265], and endometrial [266] cancer cells. Like α1 subunits, the expression level of non-pore-forming β subunits of Na V channels is altered in various cancers.…”