Acetylation-induced PCK isoenzyme transition promotes metabolic adaption of liver cancer to systemic therapy
Acetylation-induced PCK isoenzyme transition promotes metabolic adaption of liver cancer to systemic therapy
复制标题
乙酰化诱导的PCK同工酶转变促进肝癌对全身治疗的代谢适应
DOI：
10.1016/j.canlet.2021.06.016
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发表时间：
2021-06-27
期刊：
影响因子：
9.7
通讯作者：
Zhao, Xiaohang
中科院分区：
文献类型：
--
作者：
Jing, Zongpan;Gao, Jiajia;Zhao, Xiaohang
索拉非尼和乐伐替尼是获批的晚期肝癌的一线靶向治疗药物，但大多数患者会产生获得性耐药。在此，我们发现索拉非尼诱导广泛的乙酰化变化，朝向更有活力的代谢表型。代谢适应通过赖氨酸乙酰转移酶8（KAT 8）乙酰化磷酸烯醇丙酮酸羧激酶亚型2（PCK 2-K491）的Lys-491（K491）残基和PCK 1（PCK 1-K473）的Lys-473（K473）残基介导，导致同工酶从细胞质PCK 1转变为线粒体PCK 2。KAT 8催化的K491处的PCK 2乙酰化阻碍了溶酶体降解，从而增加了抗性细胞中的PCK 2水平。在体外和体内，索拉非尼耐药细胞中的PCK 2抑制显著逆转了耐药性。高水平的PCK 2预测接受索拉非尼治疗的患者的无进展生存时间较短。因此，乙酰化诱导的同工酶从PCK 1到PCK 2的转变有助于肝癌对全身治疗药物的耐药性。PCK 2可能是延迟肿瘤复发的新靶点。
Sorafenib and lenvatinib are approved first-line targeted therapies for advanced liver cancer, but most patients develop acquired resistance. Herein, we found that sorafenib induced extensive acetylation changes towards a more energetic metabolic phenotype. Metabolic adaptation was mediated via acetylation of the Lys-491 (K491) residue of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) (PCK2-K491) and Lys-473 (K473) residue of PCK1 (PCK1-K473) by the lysine acetyltransferase 8 (KAT8), resulting in isoenzyme transition from cytoplasmic PCK1 to mitochondrial PCK2. KAT8-catalyzed PCK2 acetylation at K491 impeded lysosomal degradation to increase the level of PCK2 in resistant cells. PCK2 inhibition in sorafenib-resistant cells significantly reversed drug resistance in vitro and in vivo. High levels of PCK2 predicted a shorter progression-free survival time in patients who received sorafenib treatment. Therefore, acetylation-induced isoenzyme transition from PCK1 to PCK2 contributes to resistance to systemic therapeutic drugs in liver cancer. PCK2 may be an emerging target for delaying tumor recurrence.