title: Chloroquine enhances cobalt chloride-induced leukemic cell differentiation via the suppression of autophagy at the late phase.
abstract: We previously reported that moderate hypoxia and hypoxia-mimetic agents including cobalt chloride (CoCl(2)) induce differentiation of human acute myeloid leukemia (AML) cells through hypoxia-inducible factor-1 α (HIF-1 α), which interacts with and enhances transcriptional activity of CCAAT-enhancer binding factor alpha and Runx1/AML1, two important transcriptional factors for hematopoietic cell differentiation. Here, we show that autophagy inhibitor chloroquine (CQ) increases HIF-1 α accumulation, thus potentiating CoCl(2)-induced growth arrest and differentiation of leukemic cells. Furthermore, the increased effect of CQ on differentiation induction is dependent of the inhibition of autophagosome maturation and degradation, since this sensitization could be mimicked by the suppression of expression of both lysosome-associated membrane proteins 1 and 2 (LAMP1 and LAMP2). These findings not only provide the evidence that CQ is a sensitizer for CoCl(2)-induced differentiation of leukemic cells but also possibly propose the new therapeutic strategy for differentiation induction of AML.
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhao-Wen
authors.initials: ZW
authors.lastname: Yan
authors.forename: Jia-Kai
authors.initials: JK
authors.lastname: Hou
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology*; D003035:Cobalt / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D002738:Chloroquine; D003035:Cobalt; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; C497442:HIF1A protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C497811:LAMP2 protein, human; C018021:cobaltous chloride