Department of Radiation Biology, School of Medicine, Tohoku University, Sendai 980-8575, Japan.
Kobe Research Lab, Oncolys BioPharma Inc., Kobe 650-0047, Japan.
Int J Mol Sci. 2023 Aug 15;24(16):12828. doi: 10.3390/ijms241612828.
Most solid tumors contain hypoxic and nutrient-deprived microenvironments. The cancer cells in these microenvironments have been reported to exhibit radioresistance. We have previously reported that nutrient starvation increases the expression and/or activity of ATM and DNA-PKcs, which are involved in the repair of DNA double-strand breaks induced by ionizing radiation. In the present study, to elucidate the molecular mechanisms underlying these phenomena, we investigated the roles of AMPK and FOXO3a, which play key roles in the cellular response to nutrient starvation. Nutrient starvation increased clonogenic cell survival after irradiation and increased the activity and/or expression of AMPKα, FOXO3a, ATM, DNA-PKcs, Src, EGFR, PDK1, and SOD2 in MDA-MB-231 cells. Knockdown of AMPKα using siRNA suppressed the activity and/or expression of FOXO3a, ATM, DNA-PKcs, Src, EGFR, PDK1, and SOD2 under nutrient starvation. Knockdown of FOXO3a using siRNA suppressed the activity and/or expression of AMPKα, ATM, DNA-PKcs, FOXO3a, Src, EGFR, PDK1, and SOD2 under nutrient starvation. Nutrient starvation decreased the incidence of apoptosis after 8 Gy irradiation. Knockdown of FOXO3a increased the incidence of apoptosis after irradiation under nutrient starvation. AMPK and FOXO3a appear to be key molecules that induce radioresistance under nutrient starvation and may serve as targets for radiosensitization.
大多数实体瘤都含有缺氧和营养缺乏的微环境。这些微环境中的癌细胞已被报道表现出放射抗性。我们之前曾报道过，营养饥饿会增加 ATM 和 DNA-PKcs 的表达和/或活性，而这两者都参与了由电离辐射引起的 DNA 双链断裂的修复。在本研究中，为了阐明这些现象背后的分子机制，我们研究了 AMPK 和 FOXO3a 的作用，它们在细胞对营养饥饿的反应中发挥着关键作用。营养饥饿增加了照射后的集落形成细胞存活率，并增加了 MDA-MB-231 细胞中 AMPKα、FOXO3a、ATM、DNA-PKcs、Src、EGFR、PDK1 和 SOD2 的活性和/或表达。使用 siRNA 敲低 AMPKα 会抑制营养饥饿下 FOXO3a、ATM、DNA-PKcs、Src、EGFR、PDK1 和 SOD2 的活性和/或表达。使用 siRNA 敲低 FOXO3a 会抑制营养饥饿下 AMPKα、ATM、DNA-PKcs、FOXO3a、Src、EGFR、PDK1 和 SOD2 的活性和/或表达。营养饥饿会减少 8 Gy 照射后细胞凋亡的发生率。FOXO3a 的敲低会增加营养饥饿下照射后的细胞凋亡发生率。AMPK 和 FOXO3a 似乎是营养饥饿下诱导放射抗性的关键分子，它们可能成为放射增敏的靶点。
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