Abstract
Focal adhesion kinase (FAK) activation has been reported to be associated with cell progression and metastasis in a wide variety of cancer cells. Target treatment by inhibiting FAK has achieved remarkable effects in several cancers, but the effect in ovarian cancer has not been reported. In this study, we determined the role and the underlying molecular mechanism of BI853520, a novel small chemical FAK inhibitor against ovarian cancer. Results show that phosphorylated FAK tyrosine 397 (p-FAK Y397) is highly expressed in ovarian cancer tumor tissues and cell lines (SKOV3 and OVCAR3). BI853520 treatment greatly suppresses cell proliferation, viability, migration, invasion, decreases anchorage-independent growth and motility in vitro. Besides, treatment with BI853520 increases biologic effects following combination with chemotherapy in ovarian cancer cell lines. In addition, BI853520 suppresses EMT in ovarian cancer cell lines. Mechanically, BI853520 treatment downregulates the activation of PI3K/AKT/mTOR signal pathway. Finally, mice model experiments confirm BI853520 treatment dramatically reduces tumor growth in vivo and suppresses the activation of PI3K/AKT/mTOR signal pathway. Taken together, our findings demonstrate that focal adhesion kinase inhibitor BI853520 inhibits cell proliferation, migration, invasion and EMT process through PI3K/AKT/mTOR signaling pathway in ovarian cancer, and BI853520 can offer a preclinical rationale for targeting repression of FAK in ovarian cancer.
Highlights
Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that forms important focal adhesion sites, which contains various cell surface integrins [1, 2]
Phosphorylation of FAK is needed for its kinase activity to induce downstream signals activation such as AKT and mTOR, and trigger various signaling pathways such as PI3K/AKT/mTOR signal pathway, MAPK6/ERK pathway, which was linked to aggressive tumor behaviors [5,6,7]
3.2 BI853520 inhibits phosphorylation of FAK (p‐FAK) in ovarian cancer cells
Summary
Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that forms important focal adhesion sites, which contains various cell surface integrins [1, 2]. Once these integrins recruited by signals from growth factor receptors, FAK undergoes a structural modification, inducing autophosphorylation of the tyrosine 397(Y-397) in N-terminal domain, which indicates the activation of FAK [3, 4]. PI3K/AKT/mTOR pathway plays a key role in cell proliferation, survival, cell motility, cellular metabolism and cell cycle in various tumor types [8,9,10]. The role of BI853520 in regulating PI3K/AKT/mTOR pathway of ovarian cancer cells has not yet been reported
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