Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells.
Renal cell carcinoma (RCC) is the sixth most common cancer in the US. While RCC is highly metastatic, there are few therapeutics options available for patients with metastatic RCC, and progression-free survival of patients even with the newest targeted therapeutics is only up to two years. Thus, nov...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3737191?pdf=render |
| _version_ | 1819149038689189888 |
|---|---|
| author | Omran Abu Aboud Hiromi I Wettersten Robert H Weiss |
| author_facet | Omran Abu Aboud Hiromi I Wettersten Robert H Weiss |
| author_sort | Omran Abu Aboud |
| collection | DOAJ |
| description | Renal cell carcinoma (RCC) is the sixth most common cancer in the US. While RCC is highly metastatic, there are few therapeutics options available for patients with metastatic RCC, and progression-free survival of patients even with the newest targeted therapeutics is only up to two years. Thus, novel therapeutic targets for this disease are desperately needed. Based on our previous metabolomics studies showing alteration of peroxisome proliferator-activated receptor α (PPARα) related events in both RCC patient and xenograft mice materials, this pathway was further examined in the current study in the setting of RCC. PPARα is a nuclear receptor protein that functions as a transcription factor for genes including those encoding enzymes involved in energy metabolism; while PPARα has been reported to regulate tumor growth in several cancers, it has not been evaluated in RCC. A specific PPARα antagonist, GW6471, induced both apoptosis and cell cycle arrest at G0/G1 in VHL(+) and VHL(-) RCC cell lines (786-O and Caki-1) associated with attenuation of the cell cycle regulatory proteins c-Myc, Cyclin D1, and CDK4; this data was confirmed as specific to PPARα antagonism by siRNA methods. Interestingly, when glycolysis was blocked by several methods, the cytotoxicity of GW6471 was synergistically increased, suggesting a switch to fatty acid oxidation from glycolysis and providing an entirely novel therapeutic approach for RCC. |
| first_indexed | 2024-12-22T13:55:15Z |
| format | Article |
| id | doaj.art-7be21b74d2104272979f3d4b8df9b666 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T13:55:15Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7be21b74d2104272979f3d4b8df9b6662022-12-21T18:23:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0188e7111510.1371/journal.pone.0071115Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells.Omran Abu AboudHiromi I WetterstenRobert H WeissRenal cell carcinoma (RCC) is the sixth most common cancer in the US. While RCC is highly metastatic, there are few therapeutics options available for patients with metastatic RCC, and progression-free survival of patients even with the newest targeted therapeutics is only up to two years. Thus, novel therapeutic targets for this disease are desperately needed. Based on our previous metabolomics studies showing alteration of peroxisome proliferator-activated receptor α (PPARα) related events in both RCC patient and xenograft mice materials, this pathway was further examined in the current study in the setting of RCC. PPARα is a nuclear receptor protein that functions as a transcription factor for genes including those encoding enzymes involved in energy metabolism; while PPARα has been reported to regulate tumor growth in several cancers, it has not been evaluated in RCC. A specific PPARα antagonist, GW6471, induced both apoptosis and cell cycle arrest at G0/G1 in VHL(+) and VHL(-) RCC cell lines (786-O and Caki-1) associated with attenuation of the cell cycle regulatory proteins c-Myc, Cyclin D1, and CDK4; this data was confirmed as specific to PPARα antagonism by siRNA methods. Interestingly, when glycolysis was blocked by several methods, the cytotoxicity of GW6471 was synergistically increased, suggesting a switch to fatty acid oxidation from glycolysis and providing an entirely novel therapeutic approach for RCC.http://europepmc.org/articles/PMC3737191?pdf=render |
| spellingShingle | Omran Abu Aboud Hiromi I Wettersten Robert H Weiss Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells. PLoS ONE |
| title | Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells. |
| title_full | Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells. |
| title_fullStr | Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells. |
| title_full_unstemmed | Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells. |
| title_short | Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells. |
| title_sort | inhibition of pparα induces cell cycle arrest and apoptosis and synergizes with glycolysis inhibition in kidney cancer cells |
| url | http://europepmc.org/articles/PMC3737191?pdf=render |
| work_keys_str_mv | AT omranabuaboud inhibitionofpparainducescellcyclearrestandapoptosisandsynergizeswithglycolysisinhibitioninkidneycancercells AT hiromiiwettersten inhibitionofpparainducescellcyclearrestandapoptosisandsynergizeswithglycolysisinhibitioninkidneycancercells AT roberthweiss inhibitionofpparainducescellcyclearrestandapoptosisandsynergizeswithglycolysisinhibitioninkidneycancercells |