Soluble guanylyl cyclase beta1 subunit targets epithelial-to-mesenchymal transition and downregulates Akt pathway in human endometrial and cervical cancer cells

Abstract

Endometrial and cervical cancer are among the most frequently diagnosed malignancies globally. Nitric oxide receptor-soluble guanylyl cyclase (sGC) is a heterodimeric enzyme composed of two subunits, α1 and β1. Previously we showed that sGCα1 subunit promotes cell survival, proliferation, and migration, but the role of sGCβ1 subunit has not been addressed. The aim of the present work was to study the impact of sGCβ1 restoration in proliferation, survival, migration, and cell signaling in endometrial and cervical cancer cells. We found that sGCβ1 transcript levels are reduced in endometrial and cervical tumors vs normal tissues. We confirmed nuclear enrichment of sGCβ1, unlike sGCα1. Overexpression of sGCβ1 reduced cell viability and augmented apoptotic index. Cell migration and invasion were also negatively affected. All these sGCβ1-driven effects were independent of sGC enzymatic activity. sGCβ1 reduced the expression of epithelial-to-mesenchymal transition factors such as N-cadherin and β-catenin and increased the expression of E-cadherin. sGCβ1 impacted signaling in endometrial and cervical cancer cells through significant downregulation of Akt pathway affecting some of its main targets such as GSK-3β and c-Raf. Our results show for the first time that sGCβ1 exerts several antiproliferative actions in ECC-1 and HeLa cell lines by targeting key regulatory pathways.