Abstract
SRC family kinase was documented to have vital roles in adjusting cancer cell malignant behaviors. To date, the role of c-Src, a member of SRC family kinase, in resistance to paclitaxel in human ovarian cancer cells under hypoxia has not been investigated. In the present study, we discovered that hypoxic environment suppressed paclitaxel-induced G2/M phase arrest and blockade of c-Src improved ovarian cancer cells’ sensitivity to paclitaxel. FV-429, a derivative of natural flavonoid wogonin, could suppress gene expression and activation of c-Src, followed by deteriorated Stat3 nuclear translocation and its binding to HIF-1α, resulting in paclitaxel resistance reversal through G2/M arrest potentiation. Our study demonstrated that c-Src contributed to hypoxic microenvironment-rendered paclitaxel resistance in human epithelial ovarian cancer cells by G2/M phase arrest deterioration, and through c-Src suppression, FV-429 was capable of reversing the resistance by blocking c-Src/Stat3/HIF-1α pathway.
Highlights
In solid tumor, cells in hypoxic region becomes resistant to chemotherapy and radiotherapy, the reason for which is that hypoxia helps cancer cells survive by inducing several genes involved that accelerate the progression of malignancy.[1]
It has been reported that around 69% ovarian tumors from patients overexpress hypoxia inducible factor-1α (HIF-1α),[7,8] indicating that hypoxia may be closely related to ovarian tumors
FV-429 potentiated the effect and G2/M arrest induced by paclitaxel through c-Src/Signal transducer and activator of transcription 3 (Stat3)/HIF-1α pathway deterioration in vivo
Summary
Cells in hypoxic region becomes resistant to chemotherapy and radiotherapy, the reason for which is that hypoxia helps cancer cells survive by inducing several genes involved that accelerate the progression of malignancy.[1]. Study showed that hypoxia increased G0/G1 phase percentage in ovarian cancer cells.[9] the effect of paclitaxel is based on the inhibition of microtubule depolymerization, leading to G2/M phase arrest in cancer cells, which can be weakened by the effect induced by hypoxia. FV-429, a derivative of wogonin, which is one of the main components extracted from Scutellaria baicalensis Georgi, exerted various anticancer activities.[15] It was optimized with bis (2-hydrocyethyl) amino propoxy substitution at C7 position based on wogonin.[16] FV-429 has been reported to induce apoptosis of HepG2, MDA-MB-231, BGC-823 and MGC-803 cells.[16,17,18] its ability to reverse drug resistance has not been investigated. We investigated the reversal of FV-429 on hypoxic resistance to paclitaxel on human epithelial ovarian cancer cells and the mechanism of this resistance associated with c-Src axis regulation
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