RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways

Abstract

Background/Aims: RBFOX3, an RNA-binding fox protein, plays an important role in the differentiation of neuronal development, but its role in the chemosensitivity of hepatocellular carcinoma (HCC) to 5-FU is unknown. Methods: In this study, we examined the biological functions of RBFOX3 and its effect on the chemosensitivity of HCC cells to 5-FU in vitro and in a mouse xenograft model. Results: RBFOX3 was found to have elevated expression in HCC cell lines and tissue samples, and its knockdown inhibited HCC cell proliferation. Moreover, knockdown of RBFOX3 improved the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and enhanced the apoptosis induced by 5-FU. However, overexpression of RBFOX3 reduced the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and decreased the apoptosis induced by 5-FU. We further elucidated that RBFOX3 knockdown synergized with 5-FU to inhibit the growth and invasion of HCC cells through PI3K/AKT and epithelial-mesenchymal transition (EMT) signaling, and promote apoptosis by activating the cytochrome-c/caspase signaling pathway. Finally, we validated that RBFOX3 regulated 5-FU-mediated cytotoxicity in HCC in mouse xenograft models. Conclusions: The findings from this study indicate that RBFOX3 regulates the chemosensitivity of HCC to 5-FU in vitro and in vivo. Therefore, targeting RBFOX3 may improve the inhibition of HCC growth and progression by 5-FU, and provide a novel potential therapeutic strategy for HCC.

DUXAP10 inhibition attenuates the proliferation and metastasis of hepatocellular carcinoma cells by regulation of the Wnt/β-catenin and PI3K/Akt signaling pathways

“…Our results suggested that after knockdown of DUXAP10, cell proliferation was inhibited and apoptosis was increased. Furthermore, the knockdown of DUXAP10 also inhibited PI 3 K/Akt signaling pathway [3,9,13,21]. Combining with these results, we found that by inhibiting DUXAP10 expression, the PI 3 K/Akt signaling has also attenuated.…”

“…GAPDH was used to normalize the data. The primary antibodies used: E-cadherin (Abcam, U.S.A.), N-cadeherin (Abcam, U.S.A.), Vimentin (Abcam, U.S.A.), pAkt (CST, U.S.A.), Akt (CST, U.S.A.), pJNK (CST, U.S.A.), JNK (CST, U.S.A.), GAPDH (Proteintech, U.S.A.), and β-catenin (Santa Cruz Biotechnology, U.S.A.) [13–15].…”

Preparation, Synergism, and Biocompatibility of in situ Liquid Crystals Loaded with Sinomenine and 5-Fluorouracil for Treatment of Liver Cancer

“…To test the in vitro anticancer effects of SN and/or 5-FU solutions, according to the literature 12–20 and preliminary experimental results, the stock solution concentration of 5-FU was 640 μg/mL, while that of SN was 1280 μg/mL, and the stock combination solution containing was 640 μg/mL 5-FU + 1280 μg/mL +SN. Four groups were included in the experiment as follows: negative control group (only DMEM culture medium added), 5-FU monotherapy group, SN monotherapy group, and the combination group.…”

“…As the most commonly used uracil anti-metabolite drug, 5-Fluorouracil (5-FU) 12–14 has a broad spectrum of anti-tumor effects. Further, 5-FU is the most widely used drug for treatment of HCC, and has clear therapeutic effects, making it the first choice for treatment of advanced HCC; however, minimal bioavailability, low selectivity, obvious side effects, and drug resistance limit its clinical application.…”

An integrated microchannel biosensor platform to analyse low density lactate metabolism in HepG2 cells in vitro

“…To demonstrate the ability of the biosensor array to detect variations in the cell cultures, we used the biosensor to measure lactate in HepG2 cells cultured with medium containing different drug concentrations for the rst time. 5-FU 40 and VCS 41,42 have been widely used as anticancer drugs to treat tumours for many years, and both either prevent or inhibit the process cancer cell division leading to tumour cell apoptosis. Therefore, the amount of lactate decreases due to the reduction in metabolic activity.…”