Energy metabolism in a matched model of radiation resistance for head and neck squamous cell cancer.
While radiation therapy is commonly used for treating cancer, radiation resistance can limit long-term control of the disease. In this study, we investigated the reprogramming of the energy metabolism in radiosensitive and radioresistant head and neck squamous cell carcinomas (HNSCC) using a preclinical matched model of radiation resistance. Our investigation found that radioresistant rSCC-61 cells: 1. They display increased glucose uptake and decreased fatty acid uptake; 2. They deviate from the classical Warburg effect by diverting the glycolytic flux into the pentose phosphate pathway; 3. They are more dependent on glucose than glutamine metabolism to support growth; 4. They have decreased mitochondrial oxidative phosphorylation; 5. They have enhanced fatty acid biosynthesis by increasing the expression of fatty acid synthase; and 6. They utilize endogenous fatty acids to meet the energy demands for proliferation. Inhibition of fatty acid synthase with orlistat or FASN siRNA resulted in increased cytotoxicity and sensitivity to radiation in rSCC-61 cells. These results demonstrate the potential of combination therapy using radiation and orlistat or other inhibitors of lipid and energy metabolism for treating radiation resistance in HNSCC.
Sections on a Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
Jade
J
Mims
Nidhi
N
Bansal
Manish S
MS
Bharadwaj
Xiaofei
X
Chen
Anthony J
AJ
Molina
Allen W
AW
Tsang
Cristina M
CM
Furdui
D004734:Energy Metabolism; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D018307:Neoplasms, Squamous Cell / Q000378:metabolism / Q000532:radiotherapy*; D011836:Radiation Tolerance
D064429:Fatty Acid Synthases; D005947:Glucose