Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
J Cell Mol Med. 2024 Jun;28(12):e18482. doi: 10.1111/jcmm.18482.
Hypoxia poses a significant challenge to the effectiveness of radiotherapy in head and neck squamous cell carcinoma (HNSCC) patients, and it is imperative to discover novel approaches to overcome this. In this study, we investigated the underlying mechanisms contributing to x-ray radioresistance in HPV-negative HNSCC cells under mild hypoxic conditions (1% oxygen) and explored the potential for autophagy modulation as a promising therapeutic strategy. Our findings show that HNSCC cells exposed to mild hypoxic conditions exhibit increased radioresistance, which is largely mediated by the hypoxia-inducible factor (HIF) pathway. We demonstrate that siRNA knockdown of HIF-1α and HIF-1β leads to increased radiosensitivity in HNSCC cells under hypoxia. Hypoxia-induced radioresistance was not attributed to differences in DNA double strand break repair kinetics, as these remain largely unchanged under normoxic and hypoxic conditions. Rather, we identify autophagy as a critical protective mechanism in HNSCC cells following irradiation under mild hypoxia conditions. Targeting key autophagy genes, such as BECLIN1 and BNIP3/3L, using siRNA sensitizes these cells to irradiation. Whilst autophagy's role in hypoxic radioresistance remains controversial, this study highlights the importance of autophagy modulation as a potential therapeutic approach to enhance the effectiveness of radiotherapy in HNSCC.
缺氧对头颈部鳞状细胞癌 (HNSCC) 患者放射治疗的效果构成重大挑战，因此必须寻找新的方法来克服这一挑战。在这项研究中，我们研究了 HPV 阴性 HNSCC 细胞在轻度缺氧条件（1%氧气）下产生 X 射线辐射抗性的潜在机制，并探讨了自噬调节作为一种有前途的治疗策略的潜力。我们的研究结果表明，暴露于轻度缺氧条件下的 HNSCC 细胞表现出增强的辐射抗性，这在很大程度上是由缺氧诱导因子 (HIF) 途径介导的。我们证明，在缺氧条件下，用 siRNA 敲低 HIF-1α 和 HIF-1β 可导致 HNSCC 细胞的放射敏感性增加。缺氧诱导的辐射抗性不是归因于 DNA 双链断裂修复动力学的差异，因为在常氧和缺氧条件下这些动力学基本保持不变。相反，我们发现自噬是 HNSCC 细胞在轻度缺氧条件下照射后一种重要的保护机制。使用 siRNA 靶向关键自噬基因，如 BECLIN1 和 BNIP3/3L，可使这些细胞对辐射敏感。虽然自噬在缺氧辐射抗性中的作用仍存在争议，但本研究强调了自噬调节作为增强 HNSCC 放射治疗效果的潜在治疗方法的重要性。
