期刊
AUTOPHAGY
卷 16, 期 1, 页码 106-122出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2019.1598752
关键词
Autophagosome accumulation; autophagy arrest; glioblastoma; PSAT1; regorafenib
类别
资金
- Chinese NSFC [81430071, 81602194, 81790251, 81821002, 81672381]
- National 973 Basic Research Program of China [2013CB911300]
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.
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