HtrA1 resensitizes multidrug-resistant hepatocellular carcinoma cells by targeting XIAP
Wanyuan Bao1, Feng Zhu1, Yunfei Duan1
1Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Soochow University, 185, Juqian Road, Changzhou 213003, Jiangsu Province, China.
Abstract:
The study aims to clarify the relation between chemosensitivity and HtrA1 expression, and the possible way HtrA1 works. Drug-resistant cell line HepG2/ADM was induced by increasing adriamycin (ADM), and eukaryotic expression vector pEGFP-N1-HtrA1 was constructed using BamHI and EcoRI restriction enzymes, after which, HepG2/ADM was transfected with pEGFP-N1-HtrA1. Resistance index (RI) of the hepatoma cell lines to different anti-cancer drugs (ADM, 5-Fu, MMC, L-OHP and VCR) was determined by MTT assay before and after HtrA1 high expression. After an HtrA1 inhibitor, NVP-LEB748 was adopted in the HtrA1 overexpressing cells, expression of proteins P-gp, MRP and XIAP (X-linked inhibitor of apoptosis protein) in HepG2/ADM cells were analyzed by western blot, and the activities of caspases 3, 7 and 9 were respectively measured using activity assay kits. The results showed that RI was negatively correlated with the expression of HtrA1, upregulated XIAP expression was resulted from the HtrA1 inhibitor, and variance of activities of caspases 3, 7 and 9 were remarkably descended with its increasing concentration. It was concluded that high expression of HtrA1 could significantly reverse multidrug resistance of hepatoma cells by targeting XIAP. HtrA1 is therefore expected to be an effective tool in the therapy of hepatocellular carcinoma.
Insights
High HtrA1 expression reverses multidrug resistance in hepatoma cells by targeting XIAP (X-linked inhibitor of apoptosis protein). This finding offers a potential new therapy for hepatocellular carcinoma.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- Hepatocellular carcinoma (HCC) often develops resistance to chemotherapy.
- Understanding mechanisms of multidrug resistance (MDR) is crucial for effective HCC treatment.
Purpose of the Study:
- To investigate the relationship between HtrA1 expression and chemosensitivity in drug-resistant hepatoma cells.
- To elucidate the mechanism by which HtrA1 influences drug resistance.
Main Methods:
- Constructed a eukaryotic expression vector for HtrA1 and transfected it into the adriamycin-resistant HepG2/ADM cell line.
- Assessed drug resistance using MTT assays before and after HtrA1 overexpression.
- Analyzed protein expression (P-gp, MRP, XIAP) and caspase activities following treatment with an HtrA1 inhibitor.
Main Results:
- HtrA1 high expression was negatively correlated with the resistance index (RI) to various anti-cancer drugs.
- An HtrA1 inhibitor upregulated XIAP expression and decreased caspase activities (caspase 3, 7, and 9).
- High HtrA1 expression reversed multidrug resistance in hepatoma cells.
Conclusions:
- HtrA1 plays a significant role in reversing multidrug resistance in hepatocellular carcinoma.
- HtrA1 targets XIAP to modulate chemosensitivity.
- HtrA1 represents a promising therapeutic target for hepatocellular carcinoma treatment.
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