Targeting of PFKFB3 with miR‐206 but not mir‐26b inhibits ovarian cancer cell proliferation and migration involving FAK downregulation

Abstract

Few studies explored the role of microRNAs (miRNAs) in the post‐transcriptional regulation of glycolytic proteins and downstream effectors in ovarian cancer cells. We recently showed that the functional activation of the cytoskeletal regulator FAK in endothelial cells is fostered by the glycolytic enhancer 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3). We tested the hypothesis that miR‐206 and mir‐26b, emerging onco‐suppressors targeting PFKFB3 in estrogen‐dependent tumors, would regulate proliferation and migration of serous epithelial ovarian cancer (EOC) cells via common glycolytic proteins, i.e., GLUT1 and PFKFB3, and downstream FAK. PFKFB3 was overexpressed in SKOV3, and its pharmacological inhibition with 3‐(3‐pyridinyl)‐1‐(4‐pyridinyl)‐2‐propen‐1‐one (3PO) significantly reduced cell proliferation and motility. Both miR‐206 and miR‐26b directly targeted PFKFB3 as evaluated by a luciferase reporter assay. However, endogenous levels of miR‐26b were higher than those of miR‐206, which was barely detectable in SKOV3 as well as OVCAR5 and CAOV3 cells. Accordingly, only the anti‐miR‐26b inhibitor concentration‐dependently increased PFKFB3 levels. While miR‐206 overexpression impaired proliferation and migration by downregulating PFKFB3 levels, the decreased PFKFB3 protein levels related to miR‐26 overexpression had no functional consequences in all EOC cell lines. Finally, consistent with the migration outcome, exogenous miR‐206 and miR‐26b induced opposite effects on the levels of total FAK and of its phosphorylated form at Tyr576/577. 3PO did not prevent miR‐26b‐induced SKOV3 migration. Overall, these results support the inverse relation between endogenous miRNA levels and their tumor‐suppressive effects and suggest that restoring miR‐206 expression represents a potential dual anti‐PFKFB3/FAK strategy to control ovarian cancer progression.

Role of microRNAs in glycolysis in gynecological tumors (Review)

“…In addition, the results of another study demonstrated that miR-206 downregulated PFKFB3 expression and negatively regulated focal adhesion kinase (FAK) post-transcription. These results indicated that miR-206 exhibits numerous roles, and may be used to control ovarian cancer characterized by FAK overexpression and resistance to chemotherapy (93).…”

“…Using dual-luciferase and bioinformatics analyses, the results of previous studies revealed PFKFB3 as a rate-limiting enzyme that regulates glycolysis. In addition, the levels of PFKFB3 are significantly increased in a variety of human tumors, ultimately expanding the glycolysis levels of tumor cells, and the corresponding levels of proliferation and metastasis (92,93). miR-206 interacts directly with the 3'UTR of PFKFB3 mRNA.…”

A Comparative Analysis of Naïve Exosomes and Enhanced Exosomes with a Focus on the Treatment Potential in Ovarian Disorders

“…Alternatively, miR-206 targets KIF2A, leading to the inhibition of cancer cell proliferation, migration, invasion, and induction of apoptosis [54]. Additionally, miR-206 targets CCND1 and CCND2, inhibiting the proliferation, progression, migration and invasion of ovarian cancer cells [55]. In estrogen-dependent tumors, this miRNA targets PFKFB3, regulating cancer cell proliferation through GLUT1, PFKFB3, and FAK [55].…”

Comparative clinical significance and biological roles of PFKFB family members in oral squamous cell carcinoma

“…Our results showed that PFKFB3 contributes to cellular proliferation and migration of OSCC. Previous study indicated that PFKFB3 regulate both of proliferation and migration of ovarian cancer by regulating cytosolic protein tyrosine kinase 2 (focal adhesion kinase) [ 63 ]. Moreover, PFKFB3 involves in the Ras signaling pathway, which is considered regulators of both proliferation and migration [ 64 ].…”