Secalonic acid D(SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant(MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed pote...Secalonic acid D(SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant(MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1,H460/MX20 and H460, MCF-7/ADR and MCF-7 cells. Furthermore, SAD induced cell G2/M phase arrest via the downregulation of cyclin B1 and the increase of CDC2 phosphorylation. Importantly, JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD, which was linked to cell apoptosis via c-Jun/Src/STAT3 pathway. To investigate the mechanisms of upregulation of c-Jun protein by SAD, the mR NA expression level and degradation of c-Jun were examined. We found that SAD did not alter the mR NA level of c-Jun but inhibited its proteasome-dependent degradation. Taken together, these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2(ABCG2)-mediated MDR cells.展开更多
基金supported by grants from the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” (No. 2018ZX09711002, China)Science and Technology Foundation of Guangdong Province (No. 2016A030312014, China)+1 种基金Guangzhou Science and Technology Program (No. 201707010048, China)from the Scientific and Technological Leading Talent Project of Guangdong Province (2015, China)
文摘Secalonic acid D(SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant(MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1,H460/MX20 and H460, MCF-7/ADR and MCF-7 cells. Furthermore, SAD induced cell G2/M phase arrest via the downregulation of cyclin B1 and the increase of CDC2 phosphorylation. Importantly, JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD, which was linked to cell apoptosis via c-Jun/Src/STAT3 pathway. To investigate the mechanisms of upregulation of c-Jun protein by SAD, the mR NA expression level and degradation of c-Jun were examined. We found that SAD did not alter the mR NA level of c-Jun but inhibited its proteasome-dependent degradation. Taken together, these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2(ABCG2)-mediated MDR cells.
