Mechanism of neem limonoids-induced cell death in cancer: Role of 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.

• Authors: Neelu Yadav, Sandeep Kumar, Rahul Kumar, Pragya Srivastava, Leimin Sun, Peter Rapali, Timothy Marlowe, Andrea Schneider, Joseph R Inigo, Jordan O'Malley, Ramesh Londonkar, Raghu Gogada, Ajay K Chaudhary, Nagendra Yadava, Dhyan Chandra
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 90 Pg. 261-71 (Jan 2016) ISSN: 1873-4596 [Electronic] United States
• PMID: 26627937 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• DNA, Mitochondrial
• Limonins
• Microtubule-Associated Proteins
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Mitochondrial Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• Caspases
• GTP Phosphohydrolases
• DNM1L protein, human
• Dynamins
• Electron Transport Complex I

Topics

• Apoptosis (drug effects)
• Azadirachta (chemistry)
• Caspases (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (physiology)
• DNA, Mitochondrial (analysis)
• Dynamins
• Electron Transport Complex I (physiology)
• GTP Phosphohydrolases (analysis)
• HCT116 Cells
• Humans
• Limonins (pharmacology)
• Microtubule-Associated Proteins (analysis)
• Mitochondrial Membrane Transport Proteins (physiology)
• Mitochondrial Permeability Transition Pore
• Mitochondrial Proteins (analysis)
• Neoplasms (drug therapy, pathology)
• Oxidative Phosphorylation
• Tumor Suppressor Protein p53 (physiology)