title: Mcl-1 expression and JNK activation induces a threshold for apoptosis in Bcl-xL-overexpressing hematopoietic cells.
abstract: The regulation of Mcl-1 expression is necessary for the induction of cancer cell apoptosis by ABTs such as ABT-737, ABT-263 and ABT-199. However, the reduction in Mcl-1 expression is not sufficient for initiating cell death in hematopoietic cancer cells with high Bcl-xL expression. Here, we demonstrate that 2-deoxyglucose (2-DG) enhanced the effect of ABT-199 to induce cell apoptosis in hematologic malignancies with up-regulated Bcl-xL expression. Our study revealed that 2-DG could decrease glucose-dependent and Akt-independent Mcl-1 expression, which is mediated by the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Moreover, the combination of 2-DG and ABT-199 triggered c-Jun NH2-terminal kinase (JNK) phosphorylation and subsequent Bcl-xL degradation, whereas 2-DG and ABT-199 alone had little effect on JNK activation. Therefore, the combination of 2-DG and ABT-199 initiated cell death through the reduction of Mcl-1 expression and JNK activation. Our study could provide a clinical theoretical basis for the use of ABT-199 in hematologic malignancies with excessive Bcl-xL expression.
authors.affiliation: Departmant of Oncology, Guizhou People's Hospital, Guizhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Departmant of Oncology, Guizhou People's Hospital, Guizhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Departmant of Oncology, Guizhou People's Hospital, Guizhou, China.
authors.forename: Shisheng
authors.initials: S
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China.
authors.forename: Chunlai
authors.initials: C
authors.lastname: Nie
mesh_terms: D000963:Antimetabolites / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000963:Antimetabolites; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D013449:Sulfonamides; D051020:bcl-X Protein; D003847:Deoxyglucose; D048055:Mitogen-Activated Protein Kinase 8; C579720:venetoclax
keywords: 2-DG; ABT-199; Apoptosis; Bcl-xL; Mcl-1