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Involvement of Akt in mitomycin C and its analog triggered cytotoxicity in MCF ‐7 and K562 cancer cells
Author(s) -
Cheng ShuYuan,
Vargas Anayatzinc,
Lee JiYoung,
Clement Cristina C.,
Champeil Elise
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13374
Subject(s) - protein kinase b , chemistry , pi3k/akt/mtor pathway , mitomycin c , k562 cells , cancer cell , cancer research , microbiology and biotechnology , phosphorylation , signal transduction , apoptosis , biochemistry , biology , cancer , genetics
Mitomycin C ( MC ) is a well‐known DNA alkylating agent. MC analog, 10‐decarbamoyl mitomycin C ( DMC ), unlike MC , has stronger effects on cancer with p53 mutation. We previously demonstrated that MC / DMC could activate p21 WAF 1/ CIP 1 in MCF ‐7 (p53‐proficient) and K562 (p53‐deficient) cells in a p53‐independent mode. This study aimed to elucidate the upstream signaling pathway of p21 WAF 1/ CIP 1 activation triggered by MC / DMC . Besides p53, Akt plays an important role on deactivating p21 WAF 1/ CIP 1 . The results showed that MC / DMC inhibited Akt in MCF ‐7 cells, but not in K562 cells. By knocking down p53, the Akt inhibition in MCF ‐7 cells was alleviated. This implied that the deactivated Akt caused by MC / DMC was p53‐dependent. With Akt activator ( SC 79), p21 WAF 1/ CIP 1 activation triggered by MC / DMC in MCF ‐7 cells was not reduced. This indicated that Akt inhibition triggered by MC / DMC was not associated with MC / DMC ‐induced p21 WAF 1/ CIP 1 activation. Label‐free quantitative proteomic profiling analysis revealed that DMC has a stronger effect on down‐regulating the PI 3K/Akt signaling pathway in MCF ‐7 cells as compared to MC . No significant effect of MC / DMC on PI 3K/Akt in K562 cells was observed. In summary, MC / DMC regulate Akt activation in a p53‐dependent manner. This Akt deactivation is not associated with p21 WAF 1/ CIP 1 activation in response to MC / DMC .