Abstract
A recent study reports the presence of a G1-lipid checkpoint that is dysregulated in clear cell renal carcinoma. A defective G1-lipid checkpoint forces these cells to utilize lipids as their energy source. Head and neck squamous cell carcinoma (HNSCC) cells with a higher percentage of G0/G1 cells (low proliferative index, LPI) are more resistant to radiation therapy compared to HNSCC cells with a lower percentage of G0/G1 cells (high proliferative index, HPI) 2. In this study, we investigated whether lipid metabolism regulates HNSCC cell cycle phase specific radiation sensitivity. Results from Fluorescent Ubiquitination-based Cell Cycle Indicator expressing Cal27 cells showed that cells in G0/G1 phase (LPI) are more resistant to radiation therapy compared to cells in S/G2/M phases (HPI). RNAseq and bioinformatics identified lipid and mitochondrial metabolism as the major intrinsic pathways that are different between HPI and LPI Cal27 cultures. Among the genes regulating lipid metabolism, mRNA levels of G0/G1 Switch 2 (G0S2) were found to be significantly higher in LPI compared to HPI Cal27 cultures. G0S2 was originally identified in blood mononuclear cells as a cell cycle protein of unknown functions3. Recent literature reports G0S2 as a negative regulator of the cytoplasmic neutral lipase, adipose triglyceride lipase (ATGL) 4. siG0S2 treatment of Cal27 LPI cultures recruited more cells into the proliferative cycle enhancing their radiation sensitivity. In contrast, inhibition of ATGL activity with atglistatin suppressed radiation induced toxicity. Furthermore, LPI cultures treated with palmitate enhanced mitochondrial respiration and increased ROS levels as well as lipid peroxidation resulting in radiation sensitization. These results support the hypothesis that G0S2 coordinates a G1-lipid checkpoint: G0/G1 cells prior to this checkpoint are resistant to radiation treatment, whereas S/G2/M cells that are beyond this checkpoint are radiation sensitive. We propose palmitate as a newly identified radiation sensitizer for HNSCC. (PMID:27956548; PMID:25229973; PMID:1930693; PMID:20676045)
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