Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition.
mTOR inhibitors are used clinically to treat renal cancer but are not curative. Here we show that autophagy is a resistance mechanism of human renal cell carcinoma (RCC) cell lines to mTOR inhibitors. RCC cell lines have high basal autophagy that is required for survival to mTOR inhibition. In RCC4...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0041831 |
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| _version_ | 1849335682862940160 |
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| author | Kevin Bray Robin Mathew Alexandria Lau Jurre J Kamphorst Jing Fan Jim Chen Hsin-Yi Chen Anahita Ghavami Mark Stein Robert S DiPaola Donna Zhang Joshua D Rabinowitz Eileen White |
| author_facet | Kevin Bray Robin Mathew Alexandria Lau Jurre J Kamphorst Jing Fan Jim Chen Hsin-Yi Chen Anahita Ghavami Mark Stein Robert S DiPaola Donna Zhang Joshua D Rabinowitz Eileen White |
| author_sort | Kevin Bray |
| collection | DOAJ |
| description | mTOR inhibitors are used clinically to treat renal cancer but are not curative. Here we show that autophagy is a resistance mechanism of human renal cell carcinoma (RCC) cell lines to mTOR inhibitors. RCC cell lines have high basal autophagy that is required for survival to mTOR inhibition. In RCC4 cells, inhibition of mTOR with CCI-779 stimulates autophagy and eliminates RIP kinases (RIPKs) and this is blocked by autophagy inhibition, which induces RIPK- and ROS-dependent necroptosis in vitro and suppresses xenograft growth. Autophagy of mitochondria is required for cell survival since mTOR inhibition turns off Nrf2 antioxidant defense. Thus, coordinate mTOR and autophagy inhibition leads to an imbalance between ROS production and defense, causing necroptosis that may enhance cancer treatment efficacy. |
| format | Article |
| id | doaj-art-6ba4d2c1b1124f52914b4f6ce3ca12ad |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-6ba4d2c1b1124f52914b4f6ce3ca12ad2025-08-20T03:45:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0177e4183110.1371/journal.pone.0041831Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition.Kevin BrayRobin MathewAlexandria LauJurre J KamphorstJing FanJim ChenHsin-Yi ChenAnahita GhavamiMark SteinRobert S DiPaolaDonna ZhangJoshua D RabinowitzEileen WhitemTOR inhibitors are used clinically to treat renal cancer but are not curative. Here we show that autophagy is a resistance mechanism of human renal cell carcinoma (RCC) cell lines to mTOR inhibitors. RCC cell lines have high basal autophagy that is required for survival to mTOR inhibition. In RCC4 cells, inhibition of mTOR with CCI-779 stimulates autophagy and eliminates RIP kinases (RIPKs) and this is blocked by autophagy inhibition, which induces RIPK- and ROS-dependent necroptosis in vitro and suppresses xenograft growth. Autophagy of mitochondria is required for cell survival since mTOR inhibition turns off Nrf2 antioxidant defense. Thus, coordinate mTOR and autophagy inhibition leads to an imbalance between ROS production and defense, causing necroptosis that may enhance cancer treatment efficacy.https://doi.org/10.1371/journal.pone.0041831 |
| spellingShingle | Kevin Bray Robin Mathew Alexandria Lau Jurre J Kamphorst Jing Fan Jim Chen Hsin-Yi Chen Anahita Ghavami Mark Stein Robert S DiPaola Donna Zhang Joshua D Rabinowitz Eileen White Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PLoS ONE |
| title | Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. |
| title_full | Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. |
| title_fullStr | Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. |
| title_full_unstemmed | Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. |
| title_short | Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. |
| title_sort | autophagy suppresses rip kinase dependent necrosis enabling survival to mtor inhibition |
| url | https://doi.org/10.1371/journal.pone.0041831 |
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