Small interfering RNA targeting STAT3 enhances the drug susceptibility of adriamycin in breast cancer cells / 中国药学杂志

ABSTRACT

OBJECTIVE: To further define the modulation effect of signal transducers and activators of transcription 3 (STAT3) in adriamycin-resistant breast cancer and to promote the clinical application of the inhibitors of STAT3 in reversing multidrug resistance in cancer. METHODS: Firstly, the levels of STAT3 and phosphorylated STAT3 (pSTAT3) expression in clinical breast cancer tissue samples were determined by Western blotting. The expression of STAT3 and pSTAT3 in adriamycin-sensitive and adriamycin-resistant breast cancer cell lines was evaluated by RT-PCR and Western blotting. Secondly, the expression of STAT3 was detected by Western blotting after blocking the STAT3 signal pathway with small interfering RNA targeting STAT3 (STAT3-siRNA). Finally, after the expression of STAT3 was blocked by STAT3-siRNA, immunofluorescence was performed to study the proliferation activity of breast cancer cells and MTT was used to determine the IC50 of the cells in order to observe whether STAT3-siRNA had any inhibitory effects on the growth of breast cancer cells and whether it could promote the efficacy of adriamycin in breast cancer cells. RESULTS: STAT3 and pSTAT3 were highly expressed both in clinical breast cancer tissue samples and in adriamycin-sensitive-and-resistant breast cancer cells. The expression of pSTAT3 in adriamycin-resistant breast cancer cells was significantly higher than in adriamycin-sensitive breast cancer cells. STAT3-siRNA conspicuously decreased the expression of STAT3 protein and inhibited the growth of adriamycin-sensitive breast cancer cells. Compared with the single application of adriamycin, IC50 of adriamycin-resistant breast cancer cells decreased by 4 fold when adriamycin was used in combinaiton with STAT3-siRNA. Meanwhile, an inhibition of the expression of the anti-apoptotic protein mediated by STAT3 was observed in adriamycin-resistant breast cancer cells. CONCLUSION: This study reveals that the development of breast cancer is related to the activation of STAT3. The activation of STAT3 in adriamycin-resistant breast cancer cells was more notable than in adriamycin-sensitive cells. The inhibition of the STAT3 pathway could improve the adriamycin sensitivity of adriamycin-resistant breast cancer cells and lead to their apoptosis. The RESULTS of this study explores the feasibility of the reversal of drug resistance in cancer by blocking STAT3 pathway and establishes the experimental basis for promoting the clinical use of the inhibitors of STAT3 pathway and the chemotherapeutics to overcome the multidrug resistance in cancer.