title: WNT16-expressing Acute Lymphoblastic Leukemia Cells are Sensitive to Autophagy Inhibitors after ER Stress Induction.
abstract: BACKGROUND
  Previous work from our group showed hypoxia can induce endoplasmic reticulum (ER) stress and block the processing of the WNT3 protein in cells engineered to express WNT3a. Acute lymphoblastic leukemia (ALL) cells with the t(1:19) translocation express the WNT16 gene, which is thought to contribute to transformation.
  
  
  RESULTS
  ER-stress blocks processing of endogenous WNT16 protein in RCH-ACV and 697 ALL cells. Biochemical analysis showed an aggregation of WNT16 proteins in the ER of stressed cells. These large protein masses cannot be completely cleared by ER-associated protein degradation, and require for additional autophagic responses. Pharmacological block of autophagy significantly increased cell death in ER-stressed ALL. Furthermore, murine cells engineered to express WNT16 are similarly sensitized.
  
  
  CONCLUSIONS
  ALL cells expressing WNT16 are sensitive to ER stress, and show enhanced killing after addition of chloroquine. These findings suggest a potential clinical application of inducers of ER stress with inhibitors of autophagy in patients with high-risk ALL.
authors.affiliation: General Biology Laboratory, School of Medicine, University of Patra, Rio, Greece.
authors.forename: Meletios
authors.initials: M
authors.lastname: Verras
authors.affiliation: Department of Radiation Oncology, Wexner Medical Center and Comprehensive Cancer Center, The Ohio State University, Columbus OH, U.S.A.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Papandreou
authors.affiliation: Department of Radiation Oncology, Wexner Medical Center and Comprehensive Cancer Center, The Ohio State University, Columbus OH, U.S.A. Nicholas.denko@osumc.edu.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Denko
mesh_terms: D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D059748:Proteolysis; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C417262:WNT16 protein, human; D051153:Wnt Proteins
keywords: ER-associated degradation; Unfolded protein response; WNT growth factors; acute lymphoblastic leukemia; tumor hypoxia