Cancer Management and Research (Jan 2023)
Enhanced Glycolysis Confers Resistance Against Photon but Not Carbon Ion Irradiation in Human Glioma Cell Lines
Abstract
Mohit Vashishta,1– 4 Vivek Kumar,1– 3 Chandan Guha,5 Xiaodong Wu,1– 3 Bilikere S Dwarakanath1– 3,6,7 1R&D Department, Shanghai Proton and Heavy Ion Center (SPHIC), Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, People’s Republic of China; 3Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, People’s Republic of China; 4Rangel College of Pharmacy, Texas A&M University, College Station, TX, USA; 5Albert Einstein College of Medicine, The Bronx, NY, USA; 6Central Research Facility, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai India; 7Indian Academy Degree College Autonomous (IADC-A), Bengaluru, Karnataka, IndiaCorrespondence: Bilikere S Dwarakanath, Indian Academy Degree College Autonomous (IADC-A), 230, Hennur Main Rd, Meganahalli, Kalyan Nagar, Bengaluru, Karnataka, 560043, India, Tel +91 9952081077, Email [email protected]: Metabolic reprogramming is a key hallmark in various malignancies and poses a challenge in achieving success with various therapies. Enhanced glycolysis is known to confer resistance against photon irradiation while the tumor response to carbon ion irradiation (CII) has not been investigated. This study aimed to investigate the effects of enhanced glycolysis on the response of human glioma cell lines to CII compared to the response to X-rays.Material and Methods: Glycolysis was stimulated using Dinitrophenol (DNP), a mild OXPHOS inhibitor, in three human glioma cell lines (U251, U87, and LN229) and assessed by monitoring glucose uptake and utilization as well as expression of regulators of glycolysis (glucose transporter protein type 1(Glut1), hexokinase-II (HKII), and Pyruvate Kinase-2 (PKM2). Radiation (X-rays and CII) induced loss of clonogenic survival growth inhibition and perturbations in cell cycle progression (G2+M block), cytogenetic damage (micronuclei formation), apoptosis, necrosis (reflecting interphase death), and cell migration (Scratch assay) were investigated as parameters of radiation response.Results: DNP (1 mM) enhanced the expression levels of GLUT1, HKII, and PKM2 by 30– 60% and glucose uptake as well as usage by nearly 3 folds in U251 cells suggesting the stimulation of glycolysis. Enhanced glycolysis attenuated the loss of clonogenic survival with D10 doses increasing by 20% to 65% in these cell lines, while no significant changes were noted following CII. Concomitantly, dose-dependent growth inhibition, and cytogenetic damage as well as apoptosis and necrosis induced by X-rays were also reduced by elevated glycolysis in U251 and LN229 cells by 20– 50%. However, stimulation of glycolysis enhanced the X-ray-induced cell migration, while it had negligible effect on migration following CII.Conclusion: Our results suggest that enhanced glycolysis confers resistance against X-ray-induced cell death and migration, while it may not significantly alter the cellular responses to carbon ion irradiation.Keywords: carbon ion radiotherapy, metabolic-reprogramming, radio-resistance, Warburg effect, glucose metabolism, X-rays irradiation
