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NAT10 抑制促进 ac4C 依赖性铁死亡以抵抗鼻咽癌索拉非尼耐药。

NAT10 inhibition promotes ac4C-dependent ferroptosis to counteract sorafenib resistance in nasopharyngeal carcinoma.

机构信息

Nantong University, Nantong, Jiangsu Province, China.

Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.

出版信息

Cancer Sci. 2024 Oct;115(10):3256-3272. doi: 10.1111/cas.16249. Epub 2024 Jul 22.

DOI:10.1111/cas.16249
PMID:39038928
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11447888/
Abstract

Sorafenib, an anticancer drug, has been shown to induce ferroptosis in cancer cells. However, resistance to sorafenib greatly limits its therapeutic efficacy, and the exact mechanism of resistance is not fully understood. This study investigated the role of N-Acetyltransferase 10 (NAT10) in influencing the anticancer activity of sorafenib in nasopharyngeal carcinoma (NPC) and its molecular mechanism. NAT10 expression was significantly upregulated in NPC. Mechanistically, NAT10 promotes proteins of solute carrier family 7 member 11 (SLC7A11) expression through ac4C acetylation, inhibiting sorafenib-induced ferroptosis in NPC cells. The combined application of sorafenib and the NAT10 inhibitor remodelin significantly inhibits SLC7A11 expression and promotes ferroptosis in NPC cells. In vivo knockout of NAT10 inhibited the growth of sorafenib-resistant NPC. Our findings suggest that NAT10 inhibition might be a promising therapeutic approach to enhance the anticancer activity of sorafenib.

摘要

索拉非尼是一种抗癌药物，已被证明可诱导癌细胞发生铁死亡。然而，对索拉非尼的耐药性极大地限制了其治疗效果，并且其确切的耐药机制尚不完全清楚。本研究探讨了 N-乙酰基转移酶 10（NAT10）在影响鼻咽癌（NPC）中索拉非尼的抗癌活性及其分子机制中的作用。NAT10 在 NPC 中表达明显上调。在机制上，NAT10 通过 ac4C 乙酰化促进溶质载体家族 7 成员 11（SLC7A11）蛋白的表达，抑制 NPC 细胞中索拉非尼诱导的铁死亡。索拉非尼和 NAT10 抑制剂 remodelin 的联合应用显著抑制 NPC 细胞中 SLC7A11 的表达并促进铁死亡。体内敲除 NAT10 抑制了索拉非尼耐药 NPC 的生长。我们的研究结果表明，抑制 NAT10 可能是增强索拉非尼抗癌活性的一种有前途的治疗方法。

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p53 Promotes Ferroptosis in Macrophages Treated with FeO Nanoparticles.
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