Abstract 3058: Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents

Abstract

Abstract Although cancer cells develop resistance to multiple types of anticancer agents, whether they adopt similar or differential mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. We show differential sensitivity, caspase activation, and cytokines/chemokines release in response to multiple anticancer agents. We demonstrated 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 induced apoptosis in OXPHOS-independent manner. DNA-damaging agents induced mitochondrial biogenesis accompanied by increased production of cellular and mitochondrial ROS. Mitochondrial biogenesis upregulated both mitochondrial protein-folding machinery and 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, whereas inhibition of complex II or gross complexes did not modulate the caspase activity. Interestingly, DNA damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted upon OXPHOS complex I-deficiency but not by OXPHOS complex II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross-complexes whereas a reverse trend was observed with apicidin. Together, our findings define the specific targets of apoptosis induction in response to a broad range of anticancer therapeutics, which provide a new strategy for differential mitochondrial targeting for cancer therapy. Citation Format: Sandeep Kumar, Neelu Yadav, Tim Marlowe, Ajay Chaudhary, Jianmin Wang, Jordan O'Malley, Patrick Boland, Srinivas Jayanthi, Thallapuranam Krishnaswamy Suresh Kumar, Nagendra Yadava, Dhyan Chandra. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3058. doi:10.1158/1538-7445.AM2015-3058