Fitter Mitochondria Are Associated With Radioresistance in Human Head and Neck SQD9 Cancer Cells

Abstract

The clinical management of head and neck squamous cell carcinoma (HNSCC) commonly involves chemoradiotherapy, but recurrences often occur that are associated with radioresistance. Using human SQD9 laryngeal squamous cell carcinoma cancer cells as a model, we aimed to identify metabolic changes associated with acquired radioresistance. In a top-down approach, matched radiosensitive and radioresistant SQD9 cells were generated and metabolically compared, focusing on glycolysis, oxidative phosphorylation (OXPHOS) and ROS production. The cell cycle, clonogenicity, tumor growth in mice and DNA damage-repair were assessed. Mitochondrial DNA (mtDNA) was sequenced. In a bottom-up approach, matched glycolytic and oxidative SQD9 cells were generated using FACS-sorting, and tested for their radiosensitivity/radioresistance. We found that acquired radioresistance is associated with a shift from a glycolytic to a more oxidative metabolism in SQD9 cells. The opposite was also true, as the most oxidative fraction isolated from SQD9 wild-type cells was also more radioresistant than the most glycolytic fraction. However, neither reduced hexokinase expression nor OXPHOS were directly responsible for the radioresistant phenotype. Radiosensitive and radioresistant cells had similar proliferation rates and were equally efficient for ATP production. They were equally sensitive to redox stress and had similar DNA damage repair, but radioresistant cells had an increased number of mitochondria and a higher mtDNA content. Thus, an oxidative switch is associated with but is not responsible for acquired radioresistance in human SQD9 cells. In radioresistant cells, more abundant and fitter mitochondria could help to preserve mitochondrial functions upon irradiation.

Targeting cancer-cell mitochondria and metabolism to improve radiotherapy response

“…showed that surviving cells from oncogene ablation in pancreatic cancer were reliant on OXPHOS and responsible for tumour relapse, while inhibition of OXPHOS decreased mitochondrial respiration and the ability of the surviving cells to form spheres affecting their survival [112] . Acquired radioresistance was also associated with a shift from a glycolytic to a more oxidative metabolism and to an increased number of mitochondria with a higher mtDNA content [113] .…”

“… Breast Increased PGC1α [110] Viale, A. et al Pancreatic Increased expression of OXPHOS genes [112] Grasso, D. et al. Head and neck cancer Increased OXPHOS metabolism [113] …”

Mitochondria in cancer

“…Interestingly, mitophagy appears to have a dual role in cancer treatment resistance, as both its inhibition (in colorectal CSCs) and induction (in preclinical AML models) increased the sensitivity to chemotherapeutic drugs, such as doxorubicin [271]. Mitophagy could also participate in the radioresistance of head and neck cancer cells to γ rays [272].…”

Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio

“…This suggests that tumors are able to use the mitochondrial metabolism as a substitute metabolic system for glycolysis, when they are in a high metabolic need. Therefore, this phenomenon can contribute to growth, metastatic formation and a radiation resistance phenotype (190)(191)(192). Besides the signaling-pathway-mediated and radiation-induced metabolic shift of the tumor cells, also the metabolic rewiring of the TME and CSC population can play an important role in treatment response.…”