De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling.
Malignant carcinomas that recur following therapy are typically de-differentiated and multidrug resistant (MDR). De-differentiated cancer cells acquire MDR by up-regulating reactive oxygen species (ROS)-scavenging enzymes and drug efflux pumps, but how these genes are up-regulated in response to de-...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-09-01
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| Series: | PLoS Biology |
| Online Access: | http://europepmc.org/articles/PMC4159113?pdf=render |
| _version_ | 1829135096099110912 |
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| author | Catherine A Del Vecchio Yuxiong Feng Ethan S Sokol Erik J Tillman Sandhya Sanduja Ferenc Reinhardt Piyush B Gupta |
| author_facet | Catherine A Del Vecchio Yuxiong Feng Ethan S Sokol Erik J Tillman Sandhya Sanduja Ferenc Reinhardt Piyush B Gupta |
| author_sort | Catherine A Del Vecchio |
| collection | DOAJ |
| description | Malignant carcinomas that recur following therapy are typically de-differentiated and multidrug resistant (MDR). De-differentiated cancer cells acquire MDR by up-regulating reactive oxygen species (ROS)-scavenging enzymes and drug efflux pumps, but how these genes are up-regulated in response to de-differentiation is not known. Here, we examine this question by using global transcriptional profiling to identify ROS-induced genes that are already up-regulated in de-differentiated cells, even in the absence of oxidative damage. Using this approach, we found that the Nrf2 transcription factor, which is the master regulator of cellular responses to oxidative stress, is preactivated in de-differentiated cells. In de-differentiated cells, Nrf2 is not activated by oxidation but rather through a noncanonical mechanism involving its phosphorylation by the ER membrane kinase PERK. In contrast, differentiated cells require oxidative damage to activate Nrf2. Constitutive PERK-Nrf2 signaling protects de-differentiated cells from chemotherapy by reducing ROS levels and increasing drug efflux. These findings are validated in therapy-resistant basal breast cancer cell lines and animal models, where inhibition of the PERK-Nrf2 signaling axis reversed the MDR of de-differentiated cancer cells. Additionally, analysis of patient tumor datasets showed that a PERK pathway signature correlates strongly with chemotherapy resistance, tumor grade, and overall survival. Collectively, these results indicate that de-differentiated cells up-regulate MDR genes via PERK-Nrf2 signaling and suggest that targeting this pathway could sensitize drug-resistant cells to chemotherapy. |
| first_indexed | 2024-12-14T18:18:06Z |
| format | Article |
| id | doaj.art-fea5fd64e6e84ad395b3ca4c79149cf3 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-14T18:18:06Z |
| publishDate | 2014-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-fea5fd64e6e84ad395b3ca4c79149cf32022-12-21T22:52:09ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852014-09-01129e100194510.1371/journal.pbio.1001945De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling.Catherine A Del VecchioYuxiong FengEthan S SokolErik J TillmanSandhya SandujaFerenc ReinhardtPiyush B GuptaMalignant carcinomas that recur following therapy are typically de-differentiated and multidrug resistant (MDR). De-differentiated cancer cells acquire MDR by up-regulating reactive oxygen species (ROS)-scavenging enzymes and drug efflux pumps, but how these genes are up-regulated in response to de-differentiation is not known. Here, we examine this question by using global transcriptional profiling to identify ROS-induced genes that are already up-regulated in de-differentiated cells, even in the absence of oxidative damage. Using this approach, we found that the Nrf2 transcription factor, which is the master regulator of cellular responses to oxidative stress, is preactivated in de-differentiated cells. In de-differentiated cells, Nrf2 is not activated by oxidation but rather through a noncanonical mechanism involving its phosphorylation by the ER membrane kinase PERK. In contrast, differentiated cells require oxidative damage to activate Nrf2. Constitutive PERK-Nrf2 signaling protects de-differentiated cells from chemotherapy by reducing ROS levels and increasing drug efflux. These findings are validated in therapy-resistant basal breast cancer cell lines and animal models, where inhibition of the PERK-Nrf2 signaling axis reversed the MDR of de-differentiated cancer cells. Additionally, analysis of patient tumor datasets showed that a PERK pathway signature correlates strongly with chemotherapy resistance, tumor grade, and overall survival. Collectively, these results indicate that de-differentiated cells up-regulate MDR genes via PERK-Nrf2 signaling and suggest that targeting this pathway could sensitize drug-resistant cells to chemotherapy.http://europepmc.org/articles/PMC4159113?pdf=render |
| spellingShingle | Catherine A Del Vecchio Yuxiong Feng Ethan S Sokol Erik J Tillman Sandhya Sanduja Ferenc Reinhardt Piyush B Gupta De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling. PLoS Biology |
| title | De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling. |
| title_full | De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling. |
| title_fullStr | De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling. |
| title_full_unstemmed | De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling. |
| title_short | De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling. |
| title_sort | de differentiation confers multidrug resistance via noncanonical perk nrf2 signaling |
| url | http://europepmc.org/articles/PMC4159113?pdf=render |
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