Published online Jun 14, 2017. doi: 10.3748/wjg.v23.i22.4007
Peer-review started: January 14, 2017
First decision: February 23, 2017
Revised: April 5, 2017
Accepted: May 9, 2017
Article in press: May 9, 2017
Published online: June 14, 2017
Processing time: 152 Days and 11.7 Hours
To examine the influence on apoptotic mechanisms following inhibition of polo-like kinases as therapeutically approach for cholangiocellular cancer treatment.
As most cholangiocarcinomas are chemotherapy-resistant due to mechanisms preventing tumor cell death, we investigated the effect of Cisplatin on cholangiocellular carcinoma (CCA) cell lines KMCH-1 and Mz-Ch-1. Polo-like kinases (PLK) are important regulators of the cell cycle and their inhibition is discussed as a potential therapy while PLK inhibition can regulate apoptotic mediators. Here, cells were treated with PLK inhibitor BI6727 (Volasertib), Cisplatin, and in combination of both compounds. Cell viability was assessed by MTT; apoptosis was measured by DAPI staining and caspase-3/-7 assay. Western blot and qRT-PCR were used to measure expression levels of apoptosis-related molecules Bax and Bcl-2.
The cell viability in the CCA cell lines KMCH-1 and Mz-Ch-1 was reduced in all treatment conditions compared to vehicle-treated cells. Co-treatment with BI6727 and cisplatin could even enhance the cytotoxic effect of cisplatin single treatment. Thus, co-treatment of cisplatin with BI6727 could slightly enhance the cytotoxic effect of the cisplatin in both cell lines whereas there was evidence of increased apoptosis induction solely in Mz-Ch-1 as compared to KMCH-1. Moreover, PLK inhibition decreases protein levels of Bcl-2; an effect that can be reversed by the proteasomal degradation inhibitor MG-132. In contrast, protein levels of Bax were not found to be altered by PLK inhibition. These findings indicate that cytotoxic effects of Cisplatin in Mz-Ch-1 cells can be enhanced by cotreatment with BI6727.
In conclusion, BI6727 treatment can sensitize CCA cells to cisplatin-induced apoptosis with proteasomal Bcl-2 degradation as an additional pro-apoptotic effect.
Core tip: This manuscript addresses the timely and topical roles of cell cycle/apoptosis modulating enzymes for the tumor biology of human cholangiocarcinoma. These data suggest that polo-like kinases -Inhibition by BI6727 (volasertib) sensitizes some cholangiocarcinoma cell lines to cisplatin-induced apoptosis. Our findings include an enhanced cytotoxic effect of cisplatin by co-treatment with BI6727 (volasertib) and results in decreased protein expression levels of the anti-apoptotic molecule Bcl-2, which appears to be mediated via proteasomal degradation. Taken together, these data reveal another pro-apoptotic mechanism of polo-like kinase inhibition emphasizing the potential therapeutic benefit of polo-like kinase inhibitors for the treatment of cholangiocarcinoma.