Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
Radiation Treatment Centre, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
Cell Mol Life Sci. 2023 Aug 8;80(9):242. doi: 10.1007/s00018-023-04891-9.
Radiotherapy resistance is a major obstacle to nasopharyngeal carcinoma (NPC) therapy and contributes to tumour recurrence and metastasis. Lipid metabolism is a key regulatory mechanism in cancer biology; however, its role in NPC radiotherapy resistance remains unclear. In this study, we identified hypoxia-inducible lipid droplet-associated protein (HILPDA) as a newly discovered regulator of radioresistance that induces not only lipid droplet (LD) formation but also intracellular lipid remodelling, notably changing mitochondrial cardiolipin (CL) levels. Additionally, we found that the upregulation of CL promotes mitophagy in response to irradiation exposure. Mechanistically, HILPDA inhibits PINK1-mediated CLS1 ubiquitination and degradation. The combination of a mitophagy inhibitor and irradiation significantly increases the radiosensitivity of NPC cells. Human cancer-derived data confirmed that the HILPDA-CLS1 pathway promotes NPC radioresistance. Collectively, these findings suggest that HILPDA plays a critical role in promoting NPC radioresistance and might be targeted to overcome radiotherapeutic resistance in NPC patients in the clinic.
放射抵抗是鼻咽癌（NPC）治疗的主要障碍，导致肿瘤复发和转移。脂质代谢是癌症生物学中的一个关键调节机制；然而，其在 NPC 放射抵抗中的作用尚不清楚。在本研究中，我们确定了缺氧诱导的脂滴相关蛋白（HILPDA）是一种新发现的放射抵抗调节剂，它不仅诱导脂滴（LD）形成，还诱导细胞内脂质重塑，特别是改变线粒体心磷脂（CL）水平。此外，我们发现 CL 的上调促进了对辐照暴露的线粒体自噬。在机制上，HILPDA 抑制了 PINK1 介导的 CLS1 泛素化和降解。用线粒体自噬抑制剂和辐照的联合处理显著增加了 NPC 细胞的放射敏感性。源自人类癌症的数据证实，HILPDA-CLS1 途径促进 NPC 的放射抵抗。总之，这些发现表明 HILPDA 在促进 NPC 放射抵抗中起着关键作用，并且可能成为克服 NPC 患者放射治疗抵抗的靶点。
