Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus.
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, t...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5605117?pdf=render |
| _version_ | 1818497582339457024 |
|---|---|
| author | Joseph W Briggs Ling Ren Kristi R Chakrabarti Yien Che Tsai Allan M Weissman Ryan J Hansen Daniel L Gustafson Yousuf A Khan Jonathan D Dinman Chand Khanna |
| author_facet | Joseph W Briggs Ling Ren Kristi R Chakrabarti Yien Che Tsai Allan M Weissman Ryan J Hansen Daniel L Gustafson Yousuf A Khan Jonathan D Dinman Chand Khanna |
| author_sort | Joseph W Briggs |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T18:47:17Z |
| format | Article |
| id | doaj.art-21191385288e488bb0ace408ca335cc3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T18:47:17Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-21191385288e488bb0ace408ca335cc32022-12-22T01:37:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01129e018508910.1371/journal.pone.0185089Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus.Joseph W BriggsLing RenKristi R ChakrabartiYien Che TsaiAllan M WeissmanRyan J HansenDaniel L GustafsonYousuf A KhanJonathan D DinmanChand KhannaActivation 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.http://europepmc.org/articles/PMC5605117?pdf=render |
| spellingShingle | Joseph W Briggs Ling Ren Kristi R Chakrabarti Yien Che Tsai Allan M Weissman Ryan J Hansen Daniel L Gustafson Yousuf A Khan Jonathan D Dinman Chand Khanna Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus. PLoS ONE |
| title | Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus. |
| title_full | Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus. |
| title_fullStr | Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus. |
| title_full_unstemmed | Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus. |
| title_short | Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus. |
| title_sort | activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus |
| url | http://europepmc.org/articles/PMC5605117?pdf=render |
| work_keys_str_mv | AT josephwbriggs activationoftheunfoldedproteinresponseinsarcomacellstreatedwithrapamycinortemsirolimus AT lingren activationoftheunfoldedproteinresponseinsarcomacellstreatedwithrapamycinortemsirolimus AT kristirchakrabarti activationoftheunfoldedproteinresponseinsarcomacellstreatedwithrapamycinortemsirolimus AT yienchetsai activationoftheunfoldedproteinresponseinsarcomacellstreatedwithrapamycinortemsirolimus AT allanmweissman activationoftheunfoldedproteinresponseinsarcomacellstreatedwithrapamycinortemsirolimus AT ryanjhansen activationoftheunfoldedproteinresponseinsarcomacellstreatedwithrapamycinortemsirolimus AT daniellgustafson activationoftheunfoldedproteinresponseinsarcomacellstreatedwithrapamycinortemsirolimus AT yousufakhan activationoftheunfoldedproteinresponseinsarcomacellstreatedwithrapamycinortemsirolimus AT jonathanddinman activationoftheunfoldedproteinresponseinsarcomacellstreatedwithrapamycinortemsirolimus AT chandkhanna activationoftheunfoldedproteinresponseinsarcomacellstreatedwithrapamycinortemsirolimus |