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CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma is one of most common solid cancers worldwide. Sorafenib is indicated as a treatment for advanced hepatocellular carcinoma (HCC). However, the clinical efficacy of sorafenib has been severely compromised by the development of drug resistance, and the precise mechanisms of drug resistance remain largely unknown. Here we found that a cell surface molecule, CD24, is overexpressed in tumor tissues and sorafenib-resistant hepatocellular carcinoma cell lines. Moreover, there is a positive correlation between CD24 expression levels and sorafenib resistance. In sorafenib-resistant HCC cell lines, depletion of CD24 caused a notable increase of sorafenib sensitivity. In addition, we found that CD24-related sorafenib resistance was accompanied by the activation of autophagy and can be blocked by the inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown. In further research, we found that CD24 overexpression also leads to an increase in PP2A protein production and induces the deactivation of the mTOR/AKT pathway, which enhances the level of autophagy. These results demonstrate that CD24 regulates sorafenib resistance via activating autophagy in HCC. This is the first report to describe the relationships among CD24, autophagy, and sorafenib resistance. In conclusion, the combination of autophagy modulation and CD24 targeted therapy is a promising therapeutic strategy in the treatment of HCC.

SUBMITTER: Lu S

PROVIDER: S-EPMC5974417 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma.

Lu Shuai S Yao Yao Y Xu Guolong G Zhou Chao C Zhang Yuan Y Sun Jie J Jiang Runqiu R Shao Qing Q Chen Yun Y

Cell death & disease 20180529 6

Hepatocellular carcinoma is one of most common solid cancers worldwide. Sorafenib is indicated as a treatment for advanced hepatocellular carcinoma (HCC). However, the clinical efficacy of sorafenib has been severely compromised by the development of drug resistance, and the precise mechanisms of drug resistance remain largely unknown. Here we found that a cell surface molecule, CD24, is overexpressed in tumor tissues and sorafenib-resistant hepatocellular carcinoma cell lines. Moreover, there i ...[more]

PMID: 29844385

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Project description:PurposeSorafenib is a multi-kinase inhibitor that is used as a standard treatment for advanced hepatocellular carcinoma (HCC). However, the mechanism of sorafenib resistance in HCC is still unclear. It has been shown that CISD2 expression is related to the progression and poor prognosis of HCC. Here, we show a new role for CISD2 in sorafenib resistance in HCC.MethodsBioinformatic analysis was used to detect the expression of negative regulatory genes of ferroptosis in sorafenib-resistant samples. The concentration gradient method was used to establish sorafenib-resistant HCC cells. Western blot was used to detect the protein expression of CISD2, LC3, ERK, PI3K, AKT, mTOR, and Beclin1 in HCC samples. Quantitative real-time PCR (qPCR) was used to detect gene expression. CISD2 shRNA and Beclin1 shRNA were transfected to knock down the expression of the corresponding genes. Cell viability was detected by a CCK-8 assay. ROS were detected by DCFH-DA staining, and MDA and GSH were detected with a Lipid Peroxidation MDA Assay Kit and Micro Reduced Glutathione (GSH) Assay Kit, respectively. Flow cytometry was used to detect apoptosis and the levels of ROS and iron ions.ResultsCISD2 was highly expressed in HCC cells compared with normal cells and was associated with poor prognosis in patients. Knockdown of CISD2 promoted a decrease in the viability of drug-resistant HCC cells. CISD2 knockdown promoted sorafenib-induced ferroptosis in resistant HCC cells. The levels of ROS, MDA, and iron ions increased, but the change in GSH was not obvious. Knockdown of CISD2 promoted uncontrolled autophagy in resistant HCC cells. Inhibition of autophagy attenuated CISD2 knockdown-induced ferroptosis. The autophagy promoted by CISD2 knockdown was related to Beclin1. When CISD2 and Beclin1 were inhibited, the effect on ferroptosis was correspondingly weakened.ConclusionInhibition of CISD2 promoted sorafenib-induced ferroptosis in resistant cells, and this process promoted excessive iron ion accumulation through autophagy, leading to ferroptosis. The combination of CISD2 inhibition and sorafenib treatment is an effective therapeutic strategy for resistant HCC.

Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most malignant tumors and the fourth leading cause of cancer-related death worldwide. Sorafenib is currently acknowledged as a standard therapy for advanced HCC. However, acquired resistance substantially limits the clinical efficacy of sorafenib. Therefore, further investigations of the associated risk factors are highly warranted.MethodsWe analysed a group of 78 HCC patients who received sorafenib treatment after liver resection surgery. The expression of SCAP and its correlation with sorafenib resistance in HCC clinical samples were determined by immunohistochemical analyses. Overexpression and knockdown approaches in vitro were used to characterize the functional roles of SCAP in regulating sorafenib resistance. The effects of SCAP inhibition in HCC cell lines were analysed in proliferation, apoptosis, and colony formation assays. Autophagic regulation by SCAP was assessed by immunoblotting, immunofluorescence and immunoprecipitation assays. The combinatorial effect of a SCAP inhibitor and sorafenib was tested using nude mice.ResultsHypercholesterolemia was associated with sorafenib resistance in HCC treatment. The degree of sorafenib resistance was correlated with the expression of the cholesterol sensor SCAP and consequent deposition of cholesterol. SCAP is overexpressed in HCC tissues and hepatocellular carcinoma cell lines with sorafenib resistance, while SCAP inhibition could improve sorafenib sensitivity in sorafenib-resistant HCC cells. Furthermore, we found that SCAP-mediated sorafenib resistance was related to decreased autophagy, which was connected to decreased AMPK activity. A clinically significant finding was that lycorine, a specific SCAP inhibitor, could reverse acquired resistance to sorafenib in vitro and in vivo.ConclusionsSCAP contributes to sorafenib resistance through AMPK-mediated autophagic regulation. The combination of sorafenib and SCAP targeted therapy provides a novel personalized treatment to enhance sensitivity in sorafenib-resistant HCC.

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CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma.

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CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma.

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