Critical Upstream Signals of Cytochrome c Release Induced by a Novel Bcl-2 Inhibitor

An, Jing; Chen, Yingming; Huang, Ziwei

doi:10.1074/jbc.m400295200

Cited by 96 publications

(75 citation statements)

References 63 publications

(65 reference statements)

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“…63 Whereas Bcl-2 overexpression blocked the decrease in DC(m), diminished ROS levels and prevented apoptosis in neurons and cancer cells, 64,65 Bcl-2 downregulation was associated with loss of DC(m), ROS generation and apoptosis. 66 In agreement with these data, RES provoked in MCF-7 cells a significant loss in DC(m) and a large increase in ROS that were coincident with lower levels of Bcl-2 and apoptosis induction. Moreover, Bcl-2 overexpression in MCF-7-Bcl-2 cells prevented DC(m) loss and blocked apoptosis.…”

Section: Discussionsupporting

confidence: 85%

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

205

143

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Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERa)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kB, were both inhibited by RES. The patterns for NFkB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kB and calpain protease activity. Therefore, Bcl-2 and NF-kB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells. ' 2005 Wiley-Liss, Inc.Key words: resveratrol; caspase; Bcl-2; NF-kB; apoptosis Among natural compounds with beneficial effects on human health, RES (3,4 0 ,5-trihydroxystilbene) has attracted considerable interest. This molecule, present at relevant concentrations in red wine, 1 has been associated with a lower incidence of cardiovascular disease. Different studies have also suggested a beneficial effect of RES in cancer since it inhibits proliferation and promotes death in tumor cell lines of different origins, 2-4 and, in vivo, suppresses the formation of skin 5 and mammary gland 6 tumors in rodent models of carcinogenesis.We, as well as other laboratories, have found that the ability of RES to inhibit cell viability and proliferation in the human breast cancer cell lines MCF-7 and MDA-MB-231 was unrelated to ERa status. 7,8 However, apoptotic cell death was present only in ERapositive MCF-7 and involved cell-specific regulation of the G 1 /S and G 2 /M transitions of the cell cycle. 2,8 RES properties are related to ERa since this compound has estrogenic or antiestrogenic activities depending on its concentration and the phenotype of the target cell. 9,10 ERa, in addition to its nuclear role as a transcription factor, is involved in regulating the PI3K pathway, which controls cell growth, proliferation and apoptosis. [11][12][13] In MCF-7 cells, RES induced a biphasic pattern of PI3K activity that increased at low concentrations and decreased at high concentrations. Activation of downstream PI3K effectors PKB/AKT and GSK-3 closely followed the pattern of PI3K activity. 14 The ...

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Section: Discussionsupporting

confidence: 85%

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

205

143

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“…Other apoptotic inducers such as etoposide (Figure 4b), HA14-1 (a small molecule Bcl-2 inhibitor 19,20 ) and serum starvation (data not shown) were also unable to induce Smac/DIABLO release in the cyt cÀ/À cells, while inducing both Smac/DIABLO and cyt c release in cyt c-positive cell lines.…”

Section: Discussionmentioning

confidence: 92%

Smac/DIABLO is not released from mitochondria during apoptotic signalling in cells deficient in cytochrome c

2005

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We have characterised the apoptotic defects in cells null for cytochrome c (cyt cÀ/À). Such cells treated with staurosporine (STS) exhibited translocation to the mitochondria and activation of the proapoptotic signalling molecule Bax but failed to release Smac/DIABLO from these organelles, judged by both confocal microscopy and Western blotting. While reference cells expressing cytochrome c released both it and Smac/DIABLO under a variety of conditions of apoptotic induction, we have never observed release of Smac/DIABLO from cyt cÀ/À cells. We eliminate the possibility that proteasomal degradation of cytosolically localised Smac/ DIABLO is responsible for our failure to visualise the protein outside the mitochondria. Our findings indicate an unanticipated nexus between release of cytochrome c and Smac/DIABLO from mitochondria, previously thought to be a more or less synchronised event early in apoptosis. We suggest that the failure of cyt cÀ/À cells to release Smac/DIABLO after recruitment of Bax to mitochondria represents an extreme manifestation of some inherent difference in the regulation of release of these two proteins from mitochondria.

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“…Moreover, the enhanced antiapoptotic effect of z-VAD-fmk (10 mM) against the combined treatment caused by the addition of alpha-tocopherol (100 mg/ml) suggests that ROS may also be involved in mediating caspaseindependent apoptosis (Figure 7c). The role of ROS in apoptosis has been demonstrated extensively (Phillips et al, 2002;Mikkelsen and Wardman, 2003;An et al, 2004). Upon death stimulation, ROS can induce an oxidative damage series including direct attacks on cell membranes and DNA leading to loss of membrane integrity and DNA single-strand breaks (SSBs) or DSBs (Higuchi, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…HA14-1 alone, or in combination with other cytotoxic agents, induces apoptosis selectively and effectively in many cell types including chemoresistant human cancer cells (Wang et al, 2000;Milella et al, 2002;Yamaguchi et al, 2002;Lickliter et al, 2003). Studies indicate that apoptosis induced by HA14-1 involves changes in Ca 2 þ homeostasis, DCm, Bax translocation, reactive oxygen species (ROS) generation, cytochrome c release and caspase-9/-3 activation (Wang et al, 2000;An et al, 2004). Given the unique mechanism of HA14-1 action, combining marginally cytotoxic concentrations of HA14-1 with other anticancer therapies may maximize the apoptotic effects against Bcl-2-overexpressing cancers while minimizing the nonspecific cytotoxic effects on normal tissues.…”

Section: Introductionmentioning

confidence: 99%

Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor

Chervin

Nie

et al. 2006

Oncogene

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Bcl-2 overexpression is an important mechanism underlying the aggressive behavior of prostate cancer cells and their resistance to radio-or chemotherapy. HA14-1, a recently discovered organic Bcl-2 inhibitor, potently induces apoptosis in various human cancer cells. Sequential exposure of radioresistant LNCaP (wild-type (wt) p53), LNCaP/Bcl-2 (wt p53) and PC3 (mutant p53) prostate cancer cells to a minimally cytotoxic concentration of 10 lM HA14-1 for 1 h followed by 1-6 Gy gamma radiation, resulted in a highly synergistic (combination index o1.0) induction of cell death as determined by an apoptosis assay at 72 h, and a clonogenicity assay at 12 days, after the initial treatment. The reverse treatment sequence did not cause a synergistic induction of cell death. When compared to individual treatments, cell death induced by the combined treatment was associated with dramatically increased reactive oxygen species (ROS) generation, c-Jun N-terminal kinase (JNK) activation, Bcl-2 phosphorylation, cytochrome c release, caspase-3 activation and DNA fragmentation. Exposure to either 200 lg/ml of the antioxidant alpha-tocopherol or 10 lM JNK inhibitor SP600125 before the combined treatment resulted in decreased activation of JNK and caspase-3 as well as decreased DNA fragmentation. However, treatment with the pancaspase inhibitor carbobenzoxyl-valylalanyl-aspartyl-[O-methyl]-fluoromethylketone before the combined treatment inhibited apoptosis without affecting JNK activation, and this inhibitory effect was enhanced in the presence of alpha-tocopherol or SP600125. Taken together, our results indicate that HA14-1 potently sensitizes radioresistant LNCaP and PC3 cells to gamma radiation, regardless of the status of p53. ROS and JNK are important early signals that trigger both caspasedependent and -independent cell death pathways and contribute to the apoptotic synergy induced by the combined treatments.

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Critical Upstream Signals of Cytochrome c Release Induced by a Novel Bcl-2 Inhibitor

Cited by 96 publications

References 63 publications

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Smac/DIABLO is not released from mitochondria during apoptotic signalling in cells deficient in cytochrome c

Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor

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