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Cisplatin increases B‐cell‐lymphoma‐2 expression via activation of protein kinase C and Akt2 in endometrial cancer cells
Author(s) -
Rouette Alexandre,
Parent Sophie,
Girouard Julie,
Leblanc Valérie,
Asselin Eric
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26183
Subject(s) - cisplatin , apoptosis , cancer research , protein kinase b , akt2 , chemistry , cancer cell , protein kinase c , cell culture , small hairpin rna , microbiology and biotechnology , kinase , biology , cancer , akt1 , medicine , gene knockdown , chemotherapy , biochemistry , genetics
Human carcinomas often show resistance to cisplatin and Bcl‐2 is associated with resistance to cisplatin. However, Bcl‐2 regulation on cisplatin treatment in human cancers is unknown. Here, we show a novel mechanism by which cisplatin treatment promotes resistance by increasing the expression of Bcl‐2 mRNA. Bcl‐2 mRNA and protein expression was increased in cisplatin‐resistant endometrial cancer cell lines (KLE and HEC‐1‐A), but not in cisplatin‐sensitive cell line (Ishikawa). Cisplatin‐mediated increase in Bcl‐2 expression was blocked by combination with either actinomycin D or cycloheximide. In addition, Bcl‐2 inhibition by HA14‐1 led to increased cisplatin‐induced apoptosis in KLE and HEC‐1‐A, whereas Bcl‐2 overexpression in Ishikawa led to decreased cisplatin‐induced apoptosis. Inhibition of protein kinase C (PKC) activity prevented cisplatin‐dependant increase in Bcl‐2 mRNA, and induced apoptosis in KLE cells. Furthermore, PKC inhibition was associated with decreased Akt and NF‐κB activity. Cells stably expressing shRNA for Akt isoforms revealed that Akt2 was involved in cisplatin‐dependant increase in Bcl‐2 and apoptosis. Overexpression of Akt2 in Akt2‐deficient cells led to increased Bcl‐2 expression on cisplatin treatment. Our data suggest a novel regulation pathway of Bcl‐2 by cisplatin, via the activation of PKC and Akt2, which has a profound impact on resistance to cisplatin‐induced apoptosis in endometrial cancer cells.