Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS-regulated ferroptosis  

作　　者：Xiang-jin Zheng Wen-lin Chen Jie Yi Wan Li Jin-yi Liu Wei-qi Fu Li-wen Ren Sha Li Bin-bin Ge Yi-hui Yang Yi-zhi Zhang Hong Yang Guan-hua Du Yu Wang Jin-hua Wang 

机构地区：[1]The State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Beijing 100050,China [2]Key Laboratory of Drug Target Research and Drug Screen,Institute of Materia Medica,Chinese Academy of Medical Science and Peking Union Medical College,Beijing 100050,China [3]Department of Neurosurgery,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing 100730,China [4]Department of Clinical Laboratory,Peking Union Medical College Hospital,Beijing 100730,China

出　　处：《Acta Pharmacologica Sinica》2022年第11期2977-2992,共16页中国药理学报（英文版）

基　　金：Bejing Natural Science Foundation(7212157);CAMS Innovation Fund for Medical Sciences(2021-12M-1-029);National Natural Science Foundation of China(81703536,81803584,81703565);Technology Major Projects for“Major New Drugs Innovation and Development”(2018ZX09711001-005-025,2018ZX09711001-012);Peking Union Medical College Graduate Innovation Fund(2019-1007-07).

摘　　要：Glioblastoma(GBM),a malignant brain tumor,is a world-wide health problem because of its poor prognosis and high rates of recurrence and mortality.Apolipoprotein C1(APOC1)is the smallest of apolipoproteins,implicated in many diseases.Recent studies have shown that APOC1 promotes tumorigenesis and development of several types of cancer.In this study we investigated the role of APOC1 in GBM tumorigenesis.Using in silico assays we showed that APOC1 was highly expressed in GBM tissues and its expression was closely related to GBM progression.We showed that APOC1 protein expression was markedly increased in four GBM cell lines(U251,U138,A172 and U87)compared to the normal brain glia cell lines(HEB,HA1800).In U251 cells,overexpression of APOC1 promoted cell proliferation,migration,invasion and colony information,which was reversed by APOC1 knockdown.APOC1 knockdown also markedly inhibited the growth of GBM xenografts in the ventricle of nude mice.We further demonstrated that APOC1 reduced ferroptosis by inhibiting KEAP1,promoting nuclear translocation of NRF2 and increasing expression of HO-1 and NQO1 in GBM cells.APOC1 also induced ferroptosis resistance by increasing cystathionine beta-synthase(CBS)expression,which promoted trans-sulfuration and increased GSH synthesis,ultimately leading to an increase in glutathione peroxidase-4(GPX4).Thus,APOC1 plays a key role in GBM tumorigenesis,conferring resistance to ferroptosis,and may be a promising therapeutic target for GBM.

关 键 词：GLIOBLASTOMA TUMORIGENESIS APOC1 ferroptosis lipid ROS NRF2 CBS 

分 类 号：R285.5[医药卫生—中药学]