Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma

Jingwen Jiang, Lu Zhang, Haining Chen, Yunlong Lei, Tao Zhang, Yuelong Wang, Ping Jin, Jiang Lan, Li Zhou, Zhao Huang, Bowen Li, Yuan Liu, Wei Gao, Ke Xie, Liangxue Zhou, Edouard C. Nice, Yong Peng, Yihai Cao, Yuquan Wei, Kui WangCanhua Huang

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)106-122
Number of pages17
JournalAutophagy
Volume16
Issue number1
DOIs
Publication statusPublished - 2020

Keywords

  • Autophagosome accumulation
  • autophagy arrest
  • glioblastoma
  • PSAT1
  • regorafenib

Cite this

Jiang, J., Zhang, L., Chen, H., Lei, Y., Zhang, T., Wang, Y., ... Huang, C. (2020). Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma. Autophagy, 16(1), 106-122. https://doi.org/10.1080/15548627.2019.1598752