Dephosphorylation of branched-chain α-keto acid dehydrogenase E1α (BCKDHA) promotes branched-chain amino acid catabolism and renders cancer cells resistant to X-rays by mitigating DNA damage

Abstract

Branched-chain amino acids (BCAAs) facilitate cancer cell proliferation and survival. Stresses, including X-irradiation, increase BCAA uptake. However, the role of BCAA metabolism in cancer cell survival remains unclear. Therefore, this study aimed to elucidate the role of the BCAA catabolic pathway in cancer cell survival following X-irradiation. X-irradiation dose-dependently dephosphorylated branched-chain α-keto acid dehydrogenaseE1α (BCKDHA) suggesting the activation of the BCKDH complex, which catalyzes the rate-determining step of BCAA catabolism. We considered that activation of BCKDH promoted the BCAA catabolism, which resulted in cancer cell resistance to X-irradiation. Consistent with this notion, cells with BCKDHA knockdown exhibited increased radiosensitivity, which was associated with the increase in mitotic catastrophe and residual double-strand breaks by decreasing cellular ATP levels after X-irradiation. Our results suggest that BCKDHA dephosphorylation promotes BCAA catabolism, leading to cell survival by mitigating DNA damage after X-irradiation. Thus, BCAA catabolic pathway may be a target for radiation therapy.