Abstract
Abstract Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy and its inhibition is an effective way to reverse cancer drug resistance. In the present study we report that over expression of HSP27 down-regulated MDR1 expression in MCF7/Doxorubicin (MCF7/DOX), a human breast MDR cancer cell line. In MCF7/Dox cells, mutant p53 was found to be accumulated, whereas Hsp27 level is completely depleted. Since Hsp27 was shown to enhance Akt phosphorylation and G2/M cell cycle arrest, a common pathway of Dox-induced cell death in MCF7 cells, we hypothesized that over expression of Hsp27 in resistant cell will sensitize for chemotherapy. HSP27 over expression significantly inhibited mutant p53 and MDR1 (P-gp) expression and MDR1 mRNA. The suppression of MDR1 was accompanied by partial recovery of intracellular drug accumulation and increased cytotoxicity of Doxorubicin, indicating that HSP27 reversed the MDR phenotype by inhibiting the drug efflux function of MDR1. Moreover, nuclear factor-KB activity and IKB degradation were inhibited by HSP27 over expression through down regulation of mutant p53. Interestingly, the over expression of HSP27 negatively regulated the cell growth with significant G2/M arrest of cell cycle, and it could up-regulate endogenous p21 in a p53 independent manner leading to enhanced caspase activation to promote intracellular apoptotic signaling for cell death. Taken together, our results suggested that HSP27 is down regulated in MCF7/Dox resistant cells, and when re-expressed, it down regulates MDR1 expression via p53 and NF-KB., which results in growth suppression and higher sensitivity to Doxorubicin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1744. doi:10.1158/1538-7445.AM2011-1744
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