2. Academic Validation
  3. MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma

MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma

  • Cancer Cell. 2017 Dec 11;32(6):840-855.e8. doi: 10.1016/j.ccell.2017.11.005.
Tianzhi Huang 1,  Chung Kwon Kim 1,  Angel A Alvarez 1,  Rajendra P Pangeni 1,  Xuechao Wan 1,  Xiao Song 1,  Taiping Shi 1,  Yongyong Yang 1,  Namratha Sastry 1,  Craig M Horbinski 2,  Songjian Lu 3,  Roger Stupp 1,  John A Kessler 1,  Ryo Nishikawa 4,  Ichiro Nakano 5,  Erik P Sulman 6,  Xinghua Lu 3,  Charles David James 2,  Xiao-Ming Yin 7,  Bo Hu 8,  Shi-Yuan Cheng 9
Affiliations

Affiliations

  • 1 Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 2 The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 3 Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15206, USA.
  • 4 Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama 350-1298, Japan.
  • 5 Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 6 Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 97, Houston, TX 77030, USA.
  • 7 Department of Pathology & Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA.
  • 8 Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: [email protected].
  • 9 Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: [email protected].
PMID: 29232556 DOI: 10.1016/j.ccell.2017.11.005
Abstract

ATG4B stimulates Autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses Autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and Autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM Autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy.

Keywords

ATG4B; ATG4B inhibitor NSC185058; MST4/STK26; autophagy; combination therapy; glioblastoma; glioma stem-like cells; phosphorylation; tumor response to radiation; tumorigenicity.

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