| Summary: | 碩士 === 國立嘉義大學 === 生化科技學系研究所 === 102 === Gefitinib, a selective EGFR tyrosine kinase inhibitor, has a significant activity of the antiproliferative and proapoptotic both in vitro and in vivo. Human MutS homologue-2 (MSH2) plays a central role in promoting genetic stability by correcting DNA replication errors, and defects of MSH2 have been found in lung cancer. The present study investigated the role of p38 mitogen-activated protein kinase (MAPK) signal on MSH2 expression in gefitinib-exposed human lung squamous cancer cells. The results showed that exposure of gefitinib increased MSH2 protein and mRNA levels, which was accompanied by MKK3/6-p38 MAPK activation in H520 cells. Moreover, blocking p38 MAPK activation by SB202190 significantly decreased gefitinib-induced MSH2 expression. In contract, enhancing p38 activation using constitutively active MKK6 (MKK6E) increased MSH2 protein and mRNA levels. Specific inhibition of MSH2 expression by siRNA enhanced gefitinib-induced cytotoxicity. Metformin, an anti-diabetic drug, might reduce cancer risk. In H520 cells, metformin decreased gefitinib-induced MSH2 expression and augmented the cytotoxic effect and growth inhibition by gefitinib. Transient expression of MKK6E or HA-p38 MAPK vector could abrogate metformin and gefitinib-induced synergistic cytotoxic effect in H520 cells. Together, down-regulation of MSH2 expression can be a possible strategy to enhance the sensitivity of gefitinib to human lung squamous cancer cells.
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