Lack of oxidative phosphorylation and low mitochondrial membrane potential decrease susceptibility to apoptosis and do not modulate the protective effect of Bcl-x(L) in osteosarcoma cells.
ABSTRACT We explored the role of low mitochondrial membrane potential (DeltaPsim) and the lack of oxidative phosphorylation in apoptosis by assessing the susceptibility of osteosarcoma cell lines with and without mitochondrial DNA to staurosporine-induced death. Our cells without mitochondrial DNA had low DeltaPsim and no functional oxidative phosphorylation. Contrary to our expectation, these cells were more resistant to staurosporine-induced death than were the parental cells. This reduced susceptibility was associated with decreased activation of caspase 3 but not with the mitochondrial permeability transition pore or cytochrome c release from the mitochondria. Apoptosis in both cell lines was associated with an increase in DeltaPsim. Bcl-x(L) could protect both cell types against caspase 3 activation and apoptosis by a mechanism that does not appear to be mediated by mitochondrial function or modulation of DeltaPsim. Nevertheless, we found that Bcl-x(L) expression can stimulate cell respiration in cells with mitochondrial DNA. Our results showed that the lack of functional oxidative phosphorylation and/or low mitochondrial membrane potential are associated with an antiapoptotic effect, possibly contributing to the development of some types of cancer. It also reinforces a model in which Bcl-x(L) can exert an antiapoptotic effect by stimulating oxidative phosphorylation and/or inhibiting caspase activation.
- SourceAvailable from: Awanish Kumar
Dataset: 2009 JMM, Piper bitel
Dataset: Mol. Biol. Cell-2010
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ABSTRACT: In an endeavour to develop novel and improved selective estrogen receptor modulators as anti-breast cancer agents, the benzopyran compounds have been synthesized and identified which act as potent anti-estrogen at uterine level. The present study evaluates the anti-tumor activity of 2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzo(b)pyran (CDRI-85/287) and explores the mechanism of action with a view to describe its potential to inhibit proliferation in ER- positive breast cancer cells MCF-7 and T47D. The compound decreased the expression of ERα while increased the expression of ERβ thereby altering ERα /ERβ ratio in both cell lines. Although the compound showed low binding affinity to ERs, it acted as ERα antagonist and ERβ agonist in decreasing ERE- or AP-1-mediated transcriptional activation in these cells. Transactivation studies in ERα /β - transfected MDA-MB231 cells suggested that at cyclinD1 promoter, compound antagonized the action of ERα-mediated E2 response while acted as estrogen agonist via ERβ. Further, the compound led to decreased expression of ERα-dependent proliferation markers and ERβ -dependent cell cycle progression markers. The expression of cell cycle inhibitory protein p21 was increased leading to G2/M phase arrest. In parallel, compound also interfered with EGFR activation, caused inhibition of PI-3-K/Akt pathway and subsequent induction of apoptosis via intrinsic pathway. A significant reduction in tumor mass and volume was observed in 85/287-treated mice bearing MCF-7 xenograft. We conclude that compound 85/287 exhibits significant anti-tumor activity via modulation of genomic as well as non-genomic mechanisms involved in cellular growth and arrested the cells in G2 phase in both MCF-7 and T47D breast cancer cells. Study suggests that CDRI-85/287 may have therapeutic potential in ER-positive breast cancer.Steroids 07/2013; 78(11). DOI:10.1016/j.steroids.2013.07.004 · 2.72 Impact Factor