Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma
Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma
复制标题
瑞戈非尼通过稳定胶质母细胞瘤中的 PSAT1 诱导致命性自噬停滞
DOI：
10.1080/15548627.2019.1598752
复制
发表时间：
2019-04-10
期刊：
影响因子：
13.3
通讯作者：
Huang, Canhua
中科院分区：
文献类型：
--
作者：
Jiang, Jingwen;Zhang, Lu;Huang, Canhua
摘要多形性胶质母细胞瘤（GBM）是最常见和最具侵袭性的脑肿瘤，目前尚无有效的治疗方法。因此，迫切需要开发新的有效的治疗药物用于GBM治疗。在这里，我们表明，瑞戈非尼，一种口服多激酶抑制剂，表现出优于替莫唑胺，一线化疗药物治疗GBM在体外和体内的上级疗效。从机制上讲，瑞戈非尼直接稳定PSAT 1（磷酸丝氨酸转氨酶1）（丝氨酸合成的关键酶），以触发PRKAA依赖性自噬启动并抑制RAB 11 A介导的自噬体-溶酶体融合，导致GBM细胞中的致死性自噬停滞。PSAT 1维持在高水平对于瑞格非尼诱导的GBM抑制至关重要。总之，我们的数据提供了瑞戈非尼诱导的自噬停滞的新机制见解，并提出了有效治疗GBM的新范式。缩略语：3-甲基丙烯酸：3-甲基腺嘌呤; ACACA：乙酰辅酶A羧化酶α; ACTB/β-肌动蛋白：肌动蛋白，β; AMPK：腺苷一磷酸活化蛋白激酶; ATG 5：自噬相关5; CTSD：组织蛋白酶D; DN-：显性阴性; GBM：多形性胶质母细胞瘤; LAMP 1：溶酶体相关膜蛋白1; MAP 1 LC 3B/LC 3B：微管相关蛋白1轻链3 β; PIK 3C 3/VPS 34：磷脂酰肌醇3-激酶催化亚基3型; PRKAA/AMPKα：蛋白激酶AMP活化催化亚基α; PSAT 1：磷酸丝氨酸转氨酶1; SQSTM 1/p62：螯合体1; TKI：酪氨酸激酶抑制剂。
ABSTRACT GBM (glioblastoma multiforme) is the most common and aggressive brain tumor with no curative options available. Therefore, it is imperative to develop novel potent therapeutic drugs for GBM treatment. Here, we show that regorafenib, an oral multi-kinase inhibitor, exhibits superior therapeutic efficacy over temozolomide, the first-line chemotherapeutic agent for GBM treatment both in vitro and in vivo. Mechanistically, regorafenib directly stabilizes PSAT1 (phosphoserine aminotransferase 1), a critical enzyme for serine synthesis, to trigger PRKAA-dependent autophagy initiation and inhibit RAB11A-mediated autophagosome-lysosome fusion, resulting in lethal autophagy arrest in GBM cells. Maintenance of PSAT1 at a high level is essential for regorafenib-induced GBM suppression. Together, our data provide novel mechanistic insights of regorafenib-induced autophagy arrest and suggest a new paradigm for effective treatment of GBM. Abbreviations: 3-MA: 3-methyladenine; ACACA: acetyl coenzyme A carboxylase alpha; ACTB/β-actin: actin, beta; AMPK: adenosine monophosphate-activated protein kinase; ATG5: autophagy related 5; CTSD: cathepsin D; DN-: dominant-negative; GBM: glioblastoma multiforme; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PSAT1: phosphoserine aminotransferase 1; SQSTM1/p62: sequestosome 1; TKIs: tyrosine kinase inhibitors.