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  • Title: Inhibition of the JNK signaling pathway increases sensitivity of hepatocellular carcinoma cells to cisplatin by down-regulating expression of P-glycoprotein.
    Author: Liu XY, Liu SP, Jiang J, Zhang X, Zhang T.
    Journal: Eur Rev Med Pharmacol Sci; 2016; 20(6):1098-108. PubMed ID: 27049263.
    Abstract:
    OBJECTIVE: The resistance of hepatocellular carcinoma (HCC) to chemotherapy may be mediated by the c-Jun N-terminal kinase (JNK) pathway. We wished to verify the involvement of this pathway in resistance of HCC cells to cisplatin. MATERIALS AND METHODS: We used HepG2 cell line and cisplatin-resistant clone (HepG2/DDP). Expressions of drug resistance and apoptosis-related genes were analyzed by qPCR. Protein expressions were assessed by Western blot. The JNK pathway was assessed as total JNK1/2 and JNK1/2 phosphorylation. Cell growth kinetics was quantified by the CCK-8 assay, and cell apoptosis (Annexin V / propidium iodide) by flow cytometry. RESULTS: HepG2/DDP cells were more resistant and less apoptotic on cisplatin. Expression of drug-resistance genes MDR1, MRP1 and MPR2 was significantly up-regulated in HepG2/DDP cells (p < 0.05), with up-regulation of MDR1 being the highest. This was confirmed by Western blot analysis of P-glycoprotein (P-gp), MRP1 and MRP2 proteins, the proteins encoded by the above genes. Expression of anti-apoptotic genes Bcl-2 and Bcl-XL was significantly up-regulated, and expression of pro-apoptotic genes Bak and Bad was significantly reduced, in HepG2/DDP cells (p < 0.05). Cisplatin treatment of HepG2 led to increased phosphorylation of JNK1/2; the trend reversed by the inhibitor SP600125. Furthermore, cisplatin increased expression of P-gp, which was also attenuated by SP600125. Cell growth was inhibited more substantially, and cell apoptosis promoted, when HepG2 cells were exposed to both cisplatin and SP600125. CONCLUSIONS: Inhibition of the JNK signaling pathway enhances the sensitivity of HCC cells to cisplatin by down-regulating the expression of P-gp.
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