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.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-016-5260-2) contains supplementary material, which is available to authorized users.

MiR-30a-5p confers cisplatin resistance by regulating IGF1R expression in melanoma cells

“…IGF1R is a transmembrane receptor tyrosine kinase and can activate multiple downstream signaling cascades, among which the most prominent is the phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) pathway [ 31 – 33 ]. PI3-kinase/AKT signaling can act on Mdm2 and thereby negatively regulate P53 [ 34 ].…”

Identification of key genes and associated pathways in KIT/PDGFRA wild‑type gastrointestinal stromal tumors through bioinformatics analysis

“…IGF1R, a transmembrane receptor tyrosine kinase, serves a critical role in tumor transformation and malignant cell survival. IGF1R is predominantly involved in two signaling pathways: The PI3K-Akt pathway and the Ras-mitogen-activated protein kinase pathway ( 36 ). Ludovini et al ( 37 ) identified that activation of IGF1R is a necessary condition for mediating tumor cell proliferation and invasion, and is an independent poor prognostic factor in early stage non-small cell lung cancer.…”

Cell death-based approaches in treatment of the urinary tract-associated diseases: a fight for survival in the killing fields

“…Anti-androgen therapy in advanced prostate cancer 92 Cytoskeleton-targeted therapies (taxanes). Castration-resistant prostate cancer 93 Additional approaches undergoing clinical trials Sorafenib (tyrosine kinase inhibitor): castration-resistant prostate cancer 97 , 98 Olaparib (PARP inhibitor): castration-resistant prostate cancer 102 BET bromodomain protein inhibitors: cancer 103 , 130 – 157 …”