DIRAS3 Inhibits Ovarian Cancer Cell Growth by Blocking the Fibronectin-Mediated Integrin β1/FAK/AKT Signaling Pathway

Autophagy is a crucial cellular process responsible for sustaining homeostasis through the degradation and recycling of proteins and organelles, providing energy during amino acid starvation and hypoxia. In cancer, autophagy can either inhibit tumor growth or support cancer cell survival. Our previous studies have shown that re-expression of the tumor suppressor gene DIRAS3 inhibits growth of ovarian cancer cells, promotes autophagic cell death in vitro, and induces tumor dormancy in vivo. Growth factors and extracellular matrix (ECM) components can, however, inhibit DIRAS3-induced autophagic cell death. This study explores whether fibronectin (FN) can counteract the growth inhibition induced by DIRAS3 in ovarian cancer cells. FN was found to inhibit DIRAS3-induced autophagy and to partially rescue ovarian cancer cells from DIRAS3-induced cell death while reducing DIRAS3-induced inhibition of p-FAK and p-AKT. Inhibiting FAK with defactinib in ovarian cancer cells enhanced DIRAS3-induced autophagy and cell death. Re-expression of DIRAS3 and treatment with defactinib produced tumor regression in xenograft models. Our findings suggest that ECM components in the tumor microenvironment like FN enhance the activities of β1 integrin, FAK, and AKT to inhibit DIRAS3-induced autophagic cell death, thereby promoting ovarian cancer cell survival.