Energy Metabolism in a Matched Model of Radiation Resistance for Head and Neck Squamous Cell Cancer

Abstract

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.

[18F]DCP, First Generation PET Radiotracer for Diagnosis of Radiation Resistant Head and Neck Cancer

“…Redox metabolism has been known for many decades as a key mediator of the response to radiation treatment with radiation resistant cells and tumors being characterized, in general, by a pattern of low basal ROS and upregulated antioxidant systems, consistent with our findings in HNSCC (10,11).…”

Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells

“…Besides taxanes, NP formulations of orlistat may be used in combination with other chemotherapy classes, as inhibition of FASN can sensitize pancreatic or breast cancer cells to gemcitabine or 5-fluorouracil (57,58). NP formulations of orlistat may also be used with radiation, as others have shown that inhibition of FASN can sensitize head and neck squamous or prostate cancer cells to radiation (59,60). Given the strong synergy between NanoOrl and taxanes in taxane-resistant prostate cancer cells, our data warrant the further evaluation of NanoOrl for cancer therapy either alone or in combination with taxanes.…”

Multidrug Resistance-associated Protein-1 (MRP-1)-dependent Glutathione Disulfide (GSSG) Efflux as a Critical Survival Factor for Oxidant-enriched Tumorigenic Endothelial Cells

“…Equal amounts of protein (150 g) for each sample were loaded in 96-well plates along with kit standards. Sample absorbance was measured at 450 nm, and the NADPH/NADP ratio was determined according to kit protocol (40).…”