UPR-Induced Resistance to Etoposide Is Downstream of PERK and Independent of Changes in Topoisomerase IIα Levels

BACKGROUND: The unfolded protein response (UPR) is regulated by three ER-localized, transmembrane signal transducers that control distinct aspects of the UPR. We previously reported that both increased resistance to etoposide and a reduction in Topoisomerase IIα protein levels were a direct response of UPR activation, and the latter occurred independent of changes in Topo IIα mRNA levels. We have now examined the contribution of each of the three up-stream transducers of the UPR, as well as some of their downstream targets in affecting decreased expression of Topo IIα protein and increased drug resistance. PRINCIPAL FINDINGS: Our data revealed that while Ire1 activation led to Topo IIα loss at the protein level it did not contribute to changes in sensitivity to etoposide. The decreased expression of Topo IIα protein was not downstream of XBP-1, in keeping with the fact that Topo IIα transcription was not affected by ER stress. Conversely, PERK activation did not contribute to changes in Topo IIα protein levels, but it did play a significant role in the UPR-induced decreased sensitivity to etoposide. Several cellular responses downstream of PERK were examined for their potential to contribute to resistance. The ATF6 arm of the UPR did not significantly contribute to etoposide resistance within the time frame of our experiments. CONCLUSIONS AND SIGNIFICANCE: In toto, our data demonstrate that UPR-induced changes in Topo IIα protein levels are not responsible for resistance to etoposide as has been previously hypothesized, and instead demonstrate that the PERK branch plays a Topo IIα-independent role in altered sensitivity to this drug.