The Bax Subfamily of Bcl2-Related Proteins Is Essential for Apoptotic Signal Transduction by c-Jun NH<sub>2</sub>-Terminal Kinase

Lei, Kui; Nimnual, Anjaruwee S.; Zong, Wei‐Xing; Kennedy, Norman J.; Flavell, Richard A.; Thompson, Craig B.; Bar–Sagi, Dafna; Davis, Roger J.

doi:10.1128/mcb.22.13.4929-4942.2002

Cited by 454 publications

(391 citation statements)

References 72 publications

(127 reference statements)

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“…Our findings are in accord to those of Liu et al, 2001, reporting that sensitisation of MM cells toward TRAIL by chemotherapeutic is dependent on the mitochondrial pathway, in a c-Jun N-terminal kinase (JNK)-dependent manner (Vivo et al, 2003). Thus, a-TOS, although also acting via the JNK pathway (Yu et al, 2001) signalling downstream through Bax (Lei et al, 2002), promotes the receptor-dependent pathway, thereby maximizing the apoptotic potential of the cell. In conclusion, our data show that a-TOS efficiently potentiates TRAIL killing of MM cells that are highly resistant to established treatment via mitochondrial mechanisms, and prompt testing of TRAIL and a-TOS, as well as other vitamin E analogues (Birringer et al, 2003), in preclinical models of MM.…”

supporting

confidence: 89%

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

Tomasetti¹,

Rippo²,

Alleva

et al. 2004

Br J Cancer

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Malignant mesothelioma (MM) is a fatal type of neoplasia with poor therapeutic prognosis, largely due to resistance to apoptosis. We investigated the apoptotic effect of a-tocopheryl succinate (a-TOS), a strong proapoptotic agent, in combination with the immunological apoptogen TNF-related apoptosis-inducing ligand (TRAIL) on both MM and nonmalignant mesothelial cells, since MM cells show low susceptibility to the clinically intriguing TRAIL. All MM cell lines tested were sensitive to a-TOS-induced apoptosis, and exerted high sensitivity to TRAIL in the presence of subapoptotic doses of the vitamin E analogue. Neither TRAIL or a-TOS alone or in combination caused apoptosis in nonmalignant mesothelial cells. Isobologram analysis of the cytotoxicity assays revealed a synergistic interaction between the two agents in MM cells and their antagonistic effect in nonmalignant mesothelial cells. TRAILinduced apoptosis and its augmentation by a-TOS were inhibited by the caspase-8 inhibitor Z-IETD-FMK and the pan-caspase inhibitor Z-VAD-FMK. Activation of caspase-8 was required to induce apoptosis, which was amplified by a-TOS via cytochrome c release following Bid cleavage, with ensuing activation of caspase-9. Enhancement of TRAIL-induced apoptosis in MM cells by a-TOS was also associated with upregulation of the TRAIL cognate death receptors DR4 and DR5. Our results show that a-TOS and TRAIL act in synergism to kill MM cells via mitochondrial pathway, and are nontoxic to nonmalignant mesothelial cells. These findings are indicative of a novel strategy for treatment of thus far fatal MM.

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supporting

confidence: 89%

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

Tomasetti¹,

Rippo²,

Alleva

et al. 2004

Br J Cancer

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“…25 In a number of different cellular models, inhibition of both JNK and p38 prevented the translocation of Bax. [25][26][27] For peroxynitrite-induced apoptosis to occur, MLK, p38 and JNK had to be simultaneously activated, inducing Bax translocation to the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

et al. 2006

Cell Death Differ

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The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death. Peroxynitrite-induced death was prevented by overexpression of Bcl-2 and by cyclosporin A, implicating the involvement of the intrinsic apoptotic pathway. Selective inhibition of mixed lineage kinase (MLK), p38 or JNK does not attenuate the decrease in Akt phosphorylation showing that inactivation of the Akt pathway occurs independently of the MLK/MAPK pathway. Together, these results reveal that peroxynitrite-induced activation of the intrinsic apoptotic pathway involves interactions with the MLK/MAPK and Akt signaling pathways.

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“…38 JNK in response to cellular stress, such as ROS and UV light, has been reported to act as a proapoptotic signal transducer to induce mitochondrial apoptosis. [39][40][41] p38 is up-regulated by a variety of bacterial pathogens, proinflammatory cytokines, growth factors and environmental stress, which plays an important role in inflammatory, immune response, cell growth inhibition and apoptosis. The effect of SK228 on these signaling transducers is worthy of further investigation.…”

Section: Discussionmentioning

confidence: 99%

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

Huang

Hsu

Chen

et al. 2011

Intl Journal of Cancer

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Drugs in clinical use with indole structure exhibit side effects. Therefore, to search for indole compounds with more efficacy and less side effect for cancer therapy, we developed a novel indole compound SK228 and examined its effects and mechanisms on antitumor growth and invasion inhibition in cell and tumor xenografts in nude mice models. SK228 significantly inhibited growth of different lung and esophageal cancer cell lines at sub-micromolar range, but not normal lung cells. SK228 induced DNA damages mainly by producing reactive oxygen species (ROS) resulting in apoptosis. SK228 treatment increased the release of cytochrome c into the cytosol along with the increased activity of caspase-3 and -9 without affecting caspase-8, whereas these effects were attenuated by ROS inhibitor. The expression levels of BCL-2 family regulators were also affected. Moreover, low-dose SK228 significantly reduced the invasion of cancer cells. The active phosphorylated form of FAK/Paxillin signaling pathway proteins and active form of RhoA were decreased. Moreover, the F-actin cytoskeleton was disrupted after low-dose SK228 treatment. Growth of an A549 tumor cell xenograft was markedly inhibited without significant side effects. SK228-induced apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry of cleaved caspase-3 in tumors from treated mice. Our study provides the first evidence that SK228 exhibits cancer cell-specific cytotoxicity by inducing mitochondria-mediated apoptosis. In addition, SK228 inhibits cancer cell invasion via FAK/Paxillin disruption at noncytotoxic doses. SK228 can be further tested as a pharmaceutical compound for cancer treatment.There are three standard therapies for cancer treatment including surgery, radiotherapy and chemotherapy. Chemotherapy has a role either as strategic treatment for locally advanced disease or as a palliative treatment for metastatic tumors. 1,2 However, clinical use of chemotherapy is still unsatisfactory due to limited response rate, small survival benefit and poor prognosis. Therefore, the development of novel anticancer drug, which is more effective and shows less side effect for cancer patients, is urgently needed.Several studies have indicated that compounds containing indole structure are highly cytotoxic against many tumoral cell lines, and the indole ring seems to be the core nucleus of several potent tubulin polymerization inhibitors. 3 The most wildly used clinical antimicrotubule drugs containing indole structure is Vinca alkaloids. They are also known as microtubule-destabilizing agents, which includes natural compound vinblastine, vincristine and two semisynthetic derivatives, vindesine and vinorelbine. 4 Several new compounds containing indole structure isolated from natural sources or synthesized were shown to have high potential for cancer treatment. For example, indole-3-carbinol (I3C) was isolated from cruciferous vegetables with high potential for cancer therapy. I3C and its metabolites inhibited ...

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The Bax Subfamily of Bcl2-Related Proteins Is Essential for Apoptotic Signal Transduction by c-Jun NH₂-Terminal Kinase

Cited by 454 publications

References 72 publications

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

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The Bax Subfamily of Bcl2-Related Proteins Is Essential for Apoptotic Signal Transduction by c-Jun NH2-Terminal Kinase

Cited by 454 publications

References 72 publications

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

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Resources

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The Bax Subfamily of Bcl2-Related Proteins Is Essential for Apoptotic Signal Transduction by c-Jun NH₂-Terminal Kinase