索拉非尼
癌症研究
生物化学
体内
同工酶
乙酰化
生物
酶
肝细胞癌
基因
生物技术
作者
Zongpan Jing,Jiajia Gao,Jun Li,Fangfei Niu,Lusong Tian,Nan Peng,Yan Sun,Xiufeng Xie,Ying Zhu,Yan Zhao,Fang Liu,Lanping Zhou,Yulin Sun,Xiaohang Zhao
标识
DOI:10.1016/j.canlet.2021.06.016
摘要
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.
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