Open AccessActivation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus
Author(s) -
Josie P. Briggs,
Ling Ren,
Kristi R. Chakrabarti,
Ya Chea Tsai,
Allan M. Weissman,
Ryan J. Hansen,
Daniel L. Gustafson,
Yousuf A. Khan,
Jonathan D. Dinman,
Chand Khanna
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0185089
Subject(s) - temsirolimus , cancer research , sirolimus , discovery and development of mtor inhibitors , medicine , chemistry , pharmacology , microbiology and biotechnology , biology , pi3k/akt/mtor pathway , signal transduction
Activation of the unfolded protein response (UPR) in eukaryotic cells represents an evolutionarily conserved response to physiological stress. Here, we report that the mTOR inhibitors rapamycin (sirolimus) and structurally related temsirolimus are capable of inducing UPR in sarcoma cells. However, this effect appears to be distinct from the classical role for these drugs as mTOR inhibitors. Instead, we detected these compounds to be associated with ribosomes isolated from treated cells. Specifically, temsirolimus treatment resulted in protection from chemical modification of several rRNA residues previously shown to bind rapamycin in prokaryotic cells. As an application for these findings, we demonstrate maximum tumor cell growth inhibition occurring only at doses which induce UPR and which have been shown to be safely achieved in human patients. These results are significant because they challenge the paradigm for the use of these drugs as anticancer agents and reveal a connection to UPR, a conserved biological response that has been implicated in tumor growth and response to therapy. As a result, eIF2 alpha phosphorylation and Xbp-1 splicing may serve as useful biomarkers of treatment response in future clinical trials using rapamycin and rapalogs.