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

Jing Guo¹, Janice M Santiago-O'Farrill², Vivian Orellana²

¹Department of Obstetrics and Gynecology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

|August 27, 2025

Abstract:

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.

Insights

Fibronectin (FN) in ovarian cancer inhibits DIRAS3-induced autophagy and cell death by activating FAK and AKT. Combining DIRAS3 with FAK inhibitor defactinib promotes tumor regression, offering new therapeutic strategies.

Area of Science:

Cellular Biology
Cancer Research
Molecular Oncology

Background:

Autophagy is vital for cellular homeostasis and plays a dual role in cancer.
The tumor suppressor gene DIRAS3 promotes autophagic cell death in ovarian cancer.
Extracellular matrix (ECM) components can interfere with DIRAS3-mediated anti-cancer effects.

Purpose of the Study:

To investigate the role of fibronectin (FN) in modulating DIRAS3-induced autophagic cell death in ovarian cancer.
To explore the underlying molecular mechanisms involving FAK and AKT signaling pathways.

Main Methods:

Ovarian cancer cell lines were treated with DIRAS3 and/or fibronectin.
Western blotting was used to assess levels of phosphorylated FAK (p-FAK) and AKT (p-AKT).
In vivo xenograft models were utilized to evaluate tumor regression upon combined DIRAS3 and defactinib treatment.

Main Results:

Fibronectin inhibited DIRAS3-induced autophagy and conferred partial resistance to cell death.
FN treatment reduced the inhibition of p-FAK and p-AKT by DIRAS3.
Defactinib, a FAK inhibitor, enhanced DIRAS3-induced autophagy and cell death.
Co-treatment with DIRAS3 and defactinib led to significant tumor regression in vivo.

Conclusions:

ECM components like fibronectin promote ovarian cancer cell survival by activating β1 integrin, FAK, and AKT pathways, which counteract DIRAS3-induced autophagic cell death.
Targeting FAK in combination with DIRAS3 re-expression represents a promising therapeutic strategy for ovarian cancer.

Read full analysis

Keywords:

FAK autophagy fibronectin integrin ovarian cancer

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