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 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.

Cytochrome c1 in ductal carcinoma in situ of breast associated with proliferation and comedo necrosis

“…In our present in vitro study, MCF10DCIS.com cells transfected with siRNA against CYC1 significantly decreased pro‐apoptotic caspase 3 activity under anaerobic conditions compared to normoxia. Mitochondrial OXPHOS also regulates apoptosis and enhanced OXPHOS function increased intracellular oxidative stress and apoptosis . Ducts in DCIS are frequently enlarged beyond 200 μm in diameter, although diffusion of oxygen from periductal vessels into ducts is limited to 100 μm, suggesting that the center of DCIS becomes poorly oxygenated .…”

“…Mitochondrial OXPHOS also regulates apoptosis and enhanced OXPHOS function increased intracellular oxidative stress and apoptosis. (35,38,39) Ducts in DCIS are frequently enlarged beyond 200 lm in diameter, although diffusion of oxygen from periductal vessels into ducts is limited to 100 lm, suggesting that the center of DCIS becomes poorly oxygenated. (24) Taken together with these previous findings and our present results, mitochondrial OXPHOS is suggested to play an important role in energy production of DCIS, at the early stages of breast carcinoma, and elevated OXPHOS activity through CYC1 overexpression might cause both increased proliferation activity and central comedo necrosis in DCIS.…”

Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

“…In particular, the topoisomerase 2 inhibitors studied here are known to induce oxidative stress [45, 46]. Cellular DNA damage also increases oxidative stress [47], mediated at least in part by the p53 or H2AX/Nox1/Rac1 pathway [48].…”

Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype

“…This may highlight the cell attempting to increase its suddenly lower ROS levels. High doses of NAC paradoxically increase mitochondrial mass and mitochondrial ROS . The benefits of mitochondrial ROS are dependent on the cell's overall level of stress, which can alter energy demands and NOX activity.…”