Apatinib inhibits glycolysis by suppressing the VEGFR2/AKT1/SOX5/GLUT4 signaling pathway in ovarian cancer cells

Abstract

Background Apatinib is a tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2 (VEGFR2), and has shown encouraging therapeutic effects in various malignant tumors. As yet, however, the role of apatinib in ovarian cancer has remained unknown. Here, we sought to elucidate the role of apatinib in the in vitro and in vivo viability and proliferation of ovarian cancer cells, as well as in glucose metabolism in these cells. Methods The effects of apatinib on ovarian cancer cell viability and proliferation were assessed using Cell Counting Kit-8 (CCK-8) and colony formation assays, respectively. The expression of VEGFR2/AKT1/SOX5/GLUT4 pathway proteins was assessed using Western blotting, and glucose uptake and lactate production assays were used to detect glycolysis in ovarian cancer cells. SOX5 was exogenously over-expressed and silenced in ovarian cancer cells using expression vector and shRNA-based methods, respectively. RNA expression analyses were performed using RNA-seq and gene-chip-based methods. GLUT4 promoter activity was assessed using a dual-luciferase reporter assay. The expression of p-VEGFR2 (Tyr1175), p-AKT1 (Ser473), p-GSK3β (Ser9), SOX5 and GLUT4 in xenograft tissues was assessed using immunohistochemistry (IHC). Results We found that apatinib inhibited the in vitro and in vivo viability and proliferation in Hey and OVCA433 ovarian cancer cells in a dose-dependent and time-dependent manner. We also found that apatinib effectively suppressed glucose uptake and lactate production by blocking the expression of GLUT4 in these cells. In addition, we found that SOX5 predominantly rescued the inhibitory effect of apatinib on GLUT4 expression by activating its promoter. Finally, we found that apatinib regulated the expression of SOX5 by suppressing the VEGFR2/AKT1/GSK3β signaling pathway. Conclusions From our results, we conclude that apatinib suppresses the in vitro and in vivo viability and proliferation of ovarian cancer cells, as well as glycolysis by inhibiting the VEGFR2/AKT1/GSK3β/SOX5/GLUT4 signaling pathway. Apatinib may serve as a promising drug for the treatment of ovarian cancer.

Activating CD137 Signaling Promotes Sprouting Angiogenesis via Increased VEGFA Secretion and the VEGFR2/Akt/eNOS Pathway

“…Likewise, the proliferative and migratory functions were dampened when inhibiting Akt under the CD137 signaling activation condition [ 56 ]. These results are consistent with the previous studies [ 26 , 31 , 57 , 58 ].…”

MicroRNA‑665 promotes the proliferation of ovarian cancer cells by targeting SRCIN1

“…Surgical removal and chemotherapy are two current approaches to treat patients with ovarian cancer; however, the efficacy of these treatments is limited due to the development of drug resistance and recurrence of cancer (2,3). Although numerous previous clinical and experimental studies have provided novel insight into the molecular mechanisms of ovarian cancer, patients with advanced-stages of ovarian cancer still have a poor prognosis (4,5). There is an urgent need to further understand the molecular mechanisms of ovarian cancer for the development of targeted therapeutic strategies.…”

Apatinib, a Novel Tyrosine Kinase Inhibitor, Promotes ROS-Dependent Apoptosis and Autophagy via the Nrf2/HO-1 Pathway in Ovarian Cancer Cells

“…In line with previous case reports that apatinib has potential antitumor activity in patients with OC [25][26][27][28][29][30], we found it to be effective against OC cell proliferation in both a time-and concentrationdependent manner in vitro. Similarly, apatinib has been found to inhibit cell growth in breast cancer [8], NSCLC [9], colon cancer [10], hepatocellular carcinoma [11], pancreatic cancer [12], anaplastic thyroid cancer [13,14], osteosarcoma [15], and OC [31]. Interestingly, apatinib shows contrasting effects on OC cell proliferation, with no cytotoxic effects on OC cells and no alteration of the cell cycle or apoptosis in vitro.…”