Cisplatin increases B‐cell‐lymphoma‐2 expression via activation of protein kinase C and Akt2 in endometrial cancer cells

Abstract

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.

Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild‐type ovarian cancer cells

“…19 An increase in the expression of Bcl-2 mRNA and protein is associated with resistance to CDDP in CDDP-resistant endometrial cancer cell lines, but not in CDDP-sensitive cell lines. 20 Our results show that in the CDDP-resistant A2780cis cells, CDDP did not downregulate Bcl-2 but Nut3a and CDDP plus Nut3a did. Finally, CDDP alone does not decrease Bcl-2 levels, but in combination with metformin, Bcl-2 is downregulated in OVCa cells.…”

The PI3K/AKT/mTOR Pathway as a Therapeutic Target in Endometrial Cancer

“…Activation of the PI3K/AKT/mTOR pathway has also been implicated as a mechanism of resistance to standard cytotoxic agents in endometrial cancer (76,77), and combining these agents with PI3K/AKT/mTOR pathway inhibitors has resulted in improved efficacy in numerous model systems (44), including endometrial cancer models (78). In a phase I trial of temsirolimus in combination with carboplatin and paclitaxel in advanced solid tumors, 9 of 11 patients (82%) with endometrial cancer achieved objective partial responses (79).…”

Expression, activation, and role of AKT isoforms in the uterus

“…Studies using chemoresistant cell lines and RNAi have been conducted to assess the effect of individual AKT isoforms on drug resistance. Results have shown that while all three isoforms were necessary for optimal cell proliferation, apoptosis evasion, and cell survival, AKT2 was most crucial in chemoresistance (Girouard et al 2013); this is in accordance with previous studies which suggested that elevated AKT2 activation following cisplatin treatment was responsible for Bcl2 activation and reduced apoptosis (Rouette et al 2012). Finally, we have previously shown that AKT regulates PTGS2 expression in EC through the activation of the NFkB pathway; this, in turn, enables enhanced angiogenesis, tumor invasiveness, and potentially chemoresistance (St-Germain et al 2004a,b, Chaudhry & Asselin 2009).…”