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, 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.
Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, California, United States of America.
Omran
O
Abu Aboud
Hiromi I
HI
Wettersten
Robert H
RH
Weiss
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
C449302:GW 6471; D010080:Oxazoles; D047493:PPAR alpha; D016271:Proto-Oncogene Proteins c-myc; D019938:Cyclin D1; D014443:Tyrosine; D003847:Deoxyglucose; D051358:Cyclin-Dependent Kinase 4; D005947:Glucose