2. Academic Validation
  3. Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma

Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma

  • Autophagy. 2020 Jan;16(1):106-122. doi: 10.1080/15548627.2019.1598752.
Jingwen Jiang 1,  Lu Zhang 1,  Haining Chen 2,  Yunlong Lei 3,  Tao Zhang 4,  Yuelong Wang 5,  Ping Jin 1,  Jiang Lan 1,  Li Zhou 1,  Zhao Huang 1,  Bowen Li 1,  Yuan Liu 1,  Wei Gao 1,  Ke Xie 6,  Liangxue Zhou 5,  Edouard C Nice 7,  Yong Peng 1,  Yihai Cao 8,  Yuquan Wei 1,  Kui Wang 1,  Canhua Huang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
  • 2 Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
  • 3 Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, P.R. China.
  • 4 The School of Biomedical Sciences, Chengdu Medical College, Chengdu, P.R. China.
  • 5 Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
  • 6 Department of Oncology, Sichuan Provincial People's Hospital, Chengdu, P.R. China.
  • 7 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
  • 8 Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
PMID: 30909789 DOI: 10.1080/15548627.2019.1598752
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.

Keywords

Autophagosome accumulation; PSAT1; autophagy arrest; glioblastoma; regorafenib.

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