Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Furin Prodomain Ppfurin Enhances Soce Through trpc6 Activation in Breast Cancer Cells

Version 1 : Received: 17 August 2020 / Approved: 20 August 2020 / Online: 20 August 2020 (07:41:14 CEST)

How to cite: López, J.J.; Siegfried, G.; Cantonero, C.; Descarpentrie, J.; Smani, T.; Badiola, I.; Pernot, S.; Evrard, S.; Rosado, J.A.; Khatib, A. Furin Prodomain Ppfurin Enhances Soce Through trpc6 Activation in Breast Cancer Cells. Preprints 2020, 2020080441 (doi: 10.20944/preprints202008.0441.v1). López, J.J.; Siegfried, G.; Cantonero, C.; Descarpentrie, J.; Smani, T.; Badiola, I.; Pernot, S.; Evrard, S.; Rosado, J.A.; Khatib, A. Furin Prodomain Ppfurin Enhances Soce Through trpc6 Activation in Breast Cancer Cells. Preprints 2020, 2020080441 (doi: 10.20944/preprints202008.0441.v1).

Abstract

The intracellular calcium concentration ([Ca2+]i) modulation plays a key role in the regulation of cellular growth and survival in normal cells and failure of [Ca2+]i homeostasis is involved in tumor initiation and progression. Here we show that inhibition of Furin by its naturally occurring inhibitor the prodomain ppFurin in the MDA-MB-231 breast cancer cells resulted in enhanced SOCE through TRPC6 activation that associated reduced cells malignant phenotype. Expression of ppFurin in a stable manner in MDA-MB-231 and the melanoma MDA-MB-435 cell lines inhibits Furin activity as assessed by in vitro digestion assays. Accordingly, cell transfection experiments, revealed that the ppFurin-expressing cells are unable to process adequately the PC substrates proVEGF-C and proIGF-1R. Compared to MDA-MB-435 cells, expression of ppFurin in MDA-MB-231 significantly induces Ca2+ entry which is impaired by silencing of TRPC6 expression. Analysis of TRPC6 activation revealed its up-regulated tyrosine phosphorylation in ppFurin-expressing MDA-MB-231 cells. The expression of ppFurin in MDA-MB-231 cells reduced their viability and ability to migrate and enhanced their sensitization to the apoptosis inducer hydrogen peroxide. These findings suggest that Furin inhibition by ppFurin may be a useful strategy to interfere with Ca2+ mobilization leading to breast cancer cells malignant phenotype repression and reduction of their resistance to treatments.

Subject Areas

Furin; ppFurin; Breast cancer; Calcium; SOCE; TRPC6; Viability; Migration.

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