Senescence-initiated reversal of drug resistance: specific role of XXXX .

@entity632 @entity1194 @entity17913 @entity467 @entity521 @entity43190 @entity994
The present study was undertaken to verify whether induction of senescence could be sufficient to reverse drug resistance and, if so, to determine the underlying mechanism(s). Our findings indicated that cotreatment of drug-resistant @entity521 cells with @entity632 , at sublethal concentrations, in combination with the pan-caspase inhibitor, @entity43190 , elicited a strong reduction of cell viability that occurred in a caspase-independent manner. This was accompanied by the appearance of a senescence phenotype, as evidenced by increased @entity994 / @entity994 expression and senescence-associated @entity1194 activity. Experiments using specific inhibitors of major cellular proteases other than caspases have shown that inhibition of @entity17913 , but not proteasome or @entity467 , was responsible for the senescence-initiated reversal of drug resistance. This phenomenon appeared to be general because it was valid for other drugs and drug-resistant cell lines. A nonchemical approach, through cell transfection with @entity17913 small interfering RNA, also strongly reversed drug resistance. Further investigation of the underlying mechanism revealed that @entity17913 inhibition resulted in the alteration of intracellular drug distribution. In addition, in vitro experiments have demonstrated that @entity994 / @entity994 is a substrate for @entity17913 , suggesting that inhibition of this enzyme may result in @entity994 / @entity994 stabilization and its increased accumulation. All together, these findings suggest that @entity17913 inhibition in drug-resistant cells facilitates induction of senescence and reversal of drug resistance. This may represent the basis for a novel function of @entity17913 as a cell survival molecule responsible for initiation of resistance to chemotherapy.
