title: VHL-deficient renal cancer cells gain resistance to mitochondria-activating apoptosis inducers by activating AKT through the IGF1R-PI3K pathway.
abstract: We previously developed (2-deoxyglucose)-(ABT-263) combination therapy (2DG-ABT), which induces apoptosis by activating Bak in the mitochondria of highly glycolytic cells with varied genetic backgrounds. However, the rates of apoptosis induced by 2DG-ABT were lower in von Hippel-Lindau (VHL)-deficient cancer cells. The re-expression of VHL protein in these cells lowered IGF1R expression in a manner independent of oxygen concentration. Lowering IGF1R expression via small interfering RNA (siRNA) sensitized the cells to 2DG-ABT, suggesting that IGF1R interfered with the activation of apoptosis by the mitochondria. To determine which of the two pathways activated by IGF1R, the Ras-ERK pathway or the PI3K-AKT pathway, was involved in the impairment of mitochondria activation, the cells were treated with a specific inhibitor of either PI3K or ERK, and 2DG-ABT was added to activate the mitochondria. The apoptotic rates resulting from 2DG-ABT treatment were higher in the cells treated with the PI3K inhibitor, while the rates remained approximately the same in the cells treated with the ERK inhibitor. In 2DG-ABT-sensitive cells, a 4-h 2DG treatment caused the dissociation of Mcl-1 from Bak, while ABT treatment alone caused the dissociation of Bcl-xL from Bak without substantially reducing Mcl-1 levels. In 2DG-ABT-resistant cells, Mcl-1 dissociated from Bak only when AKT activity was inhibited during the 4-h 2DG treatment. Thus, in VHL-deficient cells, IGF1R activated AKT and stabilized the Bak-Mcl-1 complex, thereby conferring cell resistance to apoptosis.
authors.affiliation: Department of Anesthesiology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. rudy.yamaguchi@hushmail.com.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Yamaguchi
authors.affiliation: Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.|Precursory Research for Embryonic Science and Technology (PREST), Japan Science and Technology Agency (JST), Saitama, 332-0012, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.affiliation: Department of Anesthesiology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Hirota
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D015870:Gene Expression; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010100:Oxygen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051020:bcl-X Protein; C000597236:IGF1R protein, human
keywords: 2-deoxyglucose; ABT-263; AKT; Apoptosis; ERK1/2; PI3K; Ras