1. Mechanism of neem limonoids-induced cell death in cancer: Role of oxidative phosphorylation.
- Author
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Yadav N, Kumar S, Kumar R, Srivastava P, Sun L, Rapali P, Marlowe T, Schneider A, Inigo JR, O'Malley J, Londonkar R, Gogada R, Chaudhary AK, Yadava N, and Chandra D
- Subjects
- Caspases metabolism, Cyclin-Dependent Kinase Inhibitor p21 physiology, DNA, Mitochondrial analysis, Dynamins, Electron Transport Complex I physiology, GTP Phosphohydrolases analysis, HCT116 Cells, Humans, Microtubule-Associated Proteins analysis, Mitochondrial Membrane Transport Proteins physiology, Mitochondrial Permeability Transition Pore, Mitochondrial Proteins analysis, Neoplasms drug therapy, Tumor Suppressor Protein p53 physiology, Apoptosis drug effects, Azadirachta chemistry, Limonins pharmacology, Neoplasms pathology, Oxidative Phosphorylation
- Abstract
We have previously reported that neem limonoids (neem) induce multiple cancer cell death pathways. Here we dissect the underlying mechanisms of neem-induced apoptotic cell death in cancer. We observed that neem-induced caspase activation does not require Bax/Bak channel-mediated mitochondrial outer membrane permeabilization, permeability transition pore, and mitochondrial fragmentation. Neem enhanced mitochondrial DNA and mitochondrial biomass. While oxidative phosphorylation (OXPHOS) Complex-I activity was decreased, the activities of other OXPHOS complexes including Complex-II and -IV were unaltered. Increased reactive oxygen species (ROS) levels were associated with an increase in mitochondrial biomass and apoptosis upon neem exposure. Complex-I deficiency due to the loss of Ndufa1-encoded MWFE protein inhibited neem-induced caspase activation and apoptosis, but cell death induction was enhanced. Complex II-deficiency due to the loss of succinate dehydrogenase complex subunit C (SDHC) robustly decreased caspase activation, apoptosis, and cell death. Additionally, the ablation of Complexes-I, -III, -IV, and -V together did not inhibit caspase activation. Together, we demonstrate that neem limonoids target OXPHOS system to induce cancer cell death, which does not require upregulation or activation of proapoptotic Bcl-2 family proteins., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2016
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