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Title: Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents

Abstract

Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting thatmore » cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [2];  [3]; ORCiD logo [1]
  1. Roswell Park Cancer Institute, Buffalo, NY (United States)
  2. Univ. of Arkansas, Fayetteville, AR (United States)
  3. Pioneer Valley Life Sciences Inst., Springfield, MA (United States)
Publication Date:
Research Org.:
Roswell Park Cancer Institute, Buffalo, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1239287
Grant/Contract Number:  
FG02-01ER15161
Resource Type:
Accepted Manuscript
Journal Name:
Cell Death and Disease
Additional Journal Information:
Journal Volume: 6; Journal Issue: 11; Journal ID: ISSN 2041-4889
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Yadav, N., Kumar, S., Marlowe, T., Chaudhary, A. K., Kumar, R., Wang, J., O'Malley, J., Boland, P. M., Jayanthi, S., Kumar, T. K. S., Yadava, N., and Chandra, D. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents. United States: N. p., 2015. Web. doi:10.1038/cddis.2015.305.
Yadav, N., Kumar, S., Marlowe, T., Chaudhary, A. K., Kumar, R., Wang, J., O'Malley, J., Boland, P. M., Jayanthi, S., Kumar, T. K. S., Yadava, N., & Chandra, D. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents. United States. doi:10.1038/cddis.2015.305.
Yadav, N., Kumar, S., Marlowe, T., Chaudhary, A. K., Kumar, R., Wang, J., O'Malley, J., Boland, P. M., Jayanthi, S., Kumar, T. K. S., Yadava, N., and Chandra, D. Thu . "Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents". United States. doi:10.1038/cddis.2015.305. https://www.osti.gov/servlets/purl/1239287.
@article{osti_1239287,
title = {Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents},
author = {Yadav, N. and Kumar, S. and Marlowe, T. and Chaudhary, A. K. and Kumar, R. and Wang, J. and O'Malley, J. and Boland, P. M. and Jayanthi, S. and Kumar, T. K. S. and Yadava, N. and Chandra, D.},
abstractNote = {Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.},
doi = {10.1038/cddis.2015.305},
journal = {Cell Death and Disease},
number = 11,
volume = 6,
place = {United States},
year = {2015},
month = {11}
}

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