SLC27A4-mediated selective uptake of mono-unsaturated fatty acids promotes ferroptosis defense in hepatocellular carcinoma
SLC27A4-mediated selective uptake of mono-unsaturated fatty acids promotes ferroptosis defense in hepatocellular carcinoma
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DOI：
10.1016/j.freeradbiomed.2023.03.013
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发表时间：
2023-03-17
影响因子：
7.4
通讯作者：
Li, Jun
中科院分区：
文献类型：
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作者：
Li, Ziwen;Liao, Xinyi;Li, Jun
由脂肪酸选择性转运介导的脂质代谢异常在癌症的发生、发展和治疗失败中起重要作用。然而，酸转运蛋白异常在人类肿瘤中的生物学功能和临床意义尚不清楚。在本研究中，我们报道了溶质载体家族成员4（SLC27A4）在21种人类癌症中显著过表达，特别是在肝细胞癌（HCC），乳腺癌和卵巢癌周围富含脂肪酸的微环境中。SLC27A4表达上调与乳腺癌或卵巢癌患者的总体和无复发生存期缩短相关。脂质组学分析表明，SLC27A4的过表达显着促进单不饱和脂肪酸（MUFA）的选择性摄取，诱导高水平的含MUFA的磷脂酰胆碱和磷脂酰乙醇胺在肝癌细胞中，从而导致抗脂质过氧化和铁凋亡。重要的是，在体外和体内，沉默SLC27A4显著促进HCC对索拉非尼治疗的敏感性。我们的研究结果揭示了SLC27A4通过脂质重塑防御铁凋亡的合理作用，这可能是一个有吸引力的治疗靶点，以提高索拉非尼治疗HCC的有效性。
Aberrant lipid metabolism mediated by the selective transport of fatty acids plays vital roles in cancer initiation, progression, and therapeutic failure. However, the biological function and clinical significance of abnormal acid transporters in human cancer remain unclear. In the present study, we reported that solute carrier family member 4 (SLC27A4) is significantly overexpressed in 21 types of human cancer, especially in the fatty acids enriched microenvironment surrounding hepatocellular carcinoma (HCC), breast cancer, and ovarian cancer. Upregulated SLC27A4 expression correlated with shorter overall and relapse-free survival of patients with breast cancer, or ovarian cancer. Lipidomic analysis revealed that overexpression of SLC27A4 significantly promoted the selective uptake of mono-unsaturated fatty acids (MUFAs), which induced a high level of MUFA-containing phosphatidylcholine and phosphatidylethanolamine in HCC cells, consequently resulting in resistance to lipid peroxidation and ferroptosis. Importantly, silencing SLC27A4 significantly promoted the sensitivity HCC to sorafenib treatment, both in vitro and in vivo. Our findings revealed a plausible role for SLC27A4 ferroptosis defense via lipid remodeling, which might represent an attractive therapeutic target to increase effectiveness of sorafenib treatment in HCC.