title: GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy.
abstract: Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies including acute lymphoblastic leukemia (ALL). The BCL-2 family has an essential role in regulating GC-induced cell death. Here we show that downregulation of antiapoptotic BCL-2 family proteins, especially MCL-1, enhances GC-induced cell death. Thus we target MCL-1 by using GX15-070 (obatoclax) in ALL cells. Treatment with GX15-070 in both dexamethasone (Dex)-sensitive and -resistant ALL cells shows effective growth inhibition and cell death. GX15-070 induces caspase-3 cleavage and increases the Annexin V-positive population, which is indicative of apoptosis. Before the onset of apoptosis, GX15-070 induces LC3 conversion as well as p62 degradation, both of which are autophagic cell death markers. A pro-apoptotic molecule BAK is released from the BAK/MCL-1 complex following GX15-070 treatment. Consistently, downregulation of BAK reduces caspase-3 cleavage and cell death, but does not alter LC3 conversion. In contrast, downregulation of ATG5, an autophagy regulator, decreases LC3 conversion and cell death, but does not alter caspase-3 cleavage, suggesting that apoptosis and autophagy induced by GX15-070 are independently regulated. Downregulation of Beclin-1, which is capable of crosstalk between apoptosis and autophagy, affects GX15-070-induced cell death through apoptosis but not autophagy. Taken together, GX15-070 treatment in ALL could be an alternative regimen to overcome glucocorticoid resistance by inducing BAK-dependent apoptosis and ATG5-dependent autophagy.
authors.affiliation: Department of Internal Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: N
authors.initials: N
authors.lastname: Heidari
authors.forename: M A
authors.initials: MA
authors.lastname: Hicks
authors.forename: H
authors.initials: H
authors.lastname: Harada
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007211:Indoles; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: C502778:ATG5 protein, human; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D005938:Glucocorticoids; D007211:Indoles; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein; C520962:obatoclax