RT Journal Article
SR Electronic
T1 Activation of the Unfolded Protein Response Is Necessary and Sufficient for Reducing Topoisomerase IIα Protein Levels and Decreasing Sensitivity to Topoisomerase-Targeted Drugs
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1699
OP 1707
DO 10.1124/mol.105.014753
VO 68
IS 6
A1 Miranda D. Gray
A1 Melissa Mann
A1 John L. Nitiss
A1 Linda M. Hendershot
YR 2005
UL http://molpharm.aspetjournals.org/content/68/6/1699.abstract
AB A wide range of chemotherapeutic agents has been identified that are active against solid tumors. However, resistance remains an important obstacle to the development of curative regimens. Whereas much attention has been paid to acquired drug resistance, a variety of physiological pathways also have been described that reduce the sensitivity of previously untreated tumors to cytotoxic antitumor agents. Treatment of cells with pharmacological agents that alter the environment of the endoplasmic reticulum (ER) and activate the unfolded protein response (UPR) can render cells resistant to topoisomerase II poisons. We describe experiments showing that activation of the mammalian ER stress response is both necessary and sufficient to decrease topoisomerase IIα protein levels and to render cells resistant to etoposide, a topoisomerase II-targeting drug. This is not caused by the elevated levels of BiP that are a hallmark of this response, because a cell line that has been engineered to overexpress BiP does not show increased resistance to etoposide. The UPR was shown to be required for altered drug sensitivity, because the BiP-overexpressing cell line, which is unable to activate the UPR, did not show decreased topoisomerase II levels or increased resistance to etoposide in response to stress conditions. The transient overexpression of an unfolded protein activated the UPR and led to the concomitant loss of topoisomerase IIα protein from the cells, demonstrating that UPR activation is sufficient for the changes in topoisomerase II levels that had been observed previously with pharmacological induction of the UPR.