Failure of Bcl-2 to block mitochondrial dysfunction during TRAIL-induced apoptosis. Tumor necrosis-related apoptosis-inducing ligand.

Kim, Eunah J.; Suliman, Ayoub; Lam, A. R. H.; Srivastava, Rakesh K.

doi:10.3892/ijo.18.1.187

Cited by 30 publications

(39 citation statements)

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“…Another mechanism by which PI3k may be involved is through activation of Akt, a Ser/Thr kinase that is recruited to plasma membrane by binding to phosphoinositides through its pleckstrin homology domain. Akt has been implicated in actin reorganization and migration of microvascular endothelial cells (Morales-Ruiz et al, 2000), and a recent report suggests that activated Akt promotes cell invasion via increasing motility (Kim et al, 2001). The members of the Rho subfamily of small GTPbinding proteins are emerging as key regulators of cytoskeleton organization.…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

Chandrasekar

Mohanam

Gujrati³

et al. 2003

Oncogene

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The ability of glioma cells to migrate great distances from a primary tumor mass is the primary cause of tumor recurrence. The urokinase-type plasminogen activator (uPA) is a serine protease that can initiate proteolytic cascades, which result in remodeling of extracellular matrix and basement membrane, allowing cells to move across and through these barriers. The binding between uPA and its receptor uPAR also mediates several signaling events that seem to contribute to the evolution of a migratory phenotype. In this study, we determined how the downregulation of uPA affects the signaling pathways leading to cell migration. Stably transfecting human glioblastoma cells with antisense uPA decreased the amount of cell-bound uPA and disrupted actin cytoskeleton formation and cell migration. The phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathway has been suggested to mediate migration in various cancer cells. The antisense-uPA clones also had less phosphorylated PI3k and Akt than control cells, a finding associated with decreased cell migration, G2/M-phase arrest, and decreased clonogenic survival. Decreased activation of PI3k and the antiapoptotic factor Akt was not sufficient to induce apoptosis in the antisense-uPA clones, but staurosporine sensitized them to apoptosis to a greater extent than control cells. These results indicate that PI3k/ Akt pathway is involved in the signaling cascade required to induce cell migration and that uPA has a direct role in regulating migration.

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Section: Discussionmentioning

confidence: 99%

“…Activated Akt has been shown to promote cancer cell invasion via increased motility (Kim et al, 2001). Akt is a powerful promoter of cell survival as it antagonizes apoptosis by phosphorylating and inactivating various components of the apoptotic machinery such as Bad (Datta et al, 1997) and caspase-9 (Cardone et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

Chandrasekar

Mohanam

Gujrati³

et al. 2003

Oncogene

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“…It also seems unlikely that the observed cytochrome c release originates from a putative Bax channel, since GDNF treatment inhibits mitochondrial Bax translocation and increases mitochondrial Bcl-2 levels, a process normally capable of inhibiting cytochrome c release via a Bax-dependent pathway (for review see Tsujimoto and Shimizu, 2000). However, it has been shown recently that during tumor necrosis-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Jurkat cells, Bcl-2 overexpression fails to block mitochondrial dysfunction and does not inhibit cytochrome c release (Kim et al, 2001). It is known that formation of the cytochrome c-Apaf-1 complex (for a review see Gottlieb, 2000), rather than the presence per se of cytochrome c in the cytoplasm, is the determining factor in the activation of caspases and in the triggering of apoptosis.…”

Section: Figmentioning

confidence: 99%

GDNF Protects against Aluminum-Induced Apoptosis in Rabbits by Upregulating Bcl-2 and Bcl-XL and Inhibiting Mitochondrial Bax Translocation

Ghribi

Herman

Forbes

et al. 2001

Neurobiology of Disease

100

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Direct (intracisternal) injection of aluminum complexes into rabbit brain results in a number of similarities with the neuropathological and biochemical changes observed in Alzheimer's disease and provides the opportunity to assess early events in neurodegeneration. This mode of administration induces cytochrome c release from mitochondria, a decrease in Bcl-2 in both mitochondria and endoplasmic reticulum, Bax translocation into mitochondria, activation of caspase-3, and DNA fragmentation. Coadministration of glial cell neuronal-derived factor (GDNF) inhibits these Bcl-2 and Bax changes, upregulates Bcl-X L , and abolishes the caspase-3 activity. Furthermore, treatment with GDNF dramatically inhibits apoptosis, as assessed by the TUNEL technique for detecting DNA damage. Treatment with GDNF may represent a therapeutic strategy to reverse the neuronal death associated with Alzheimer's disease and may exert its effect on apoptosis-regulatory proteins.

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“…Overexpression of Bcl-2 and Bcl-X L seem to inhibit apoptosis induced by both FasL and TNF (17,21). However, the role of Bcl-2 in inhibiting TRAIL-mediated apoptosis is less clear because several prior reports, mostly in lymphoma cell lines, have failed to demonstrate a role for either Bcl-2 or Bcl-X L proteins in protecting cells from TRAILinduced apoptosis (22)(23)(24)(25)(26). These data suggested that TRAILinduced apoptosis was independent of mitochondria and that this drug could be used in Bcl-2-overexpressing tumors.…”

Section: Introductionmentioning

confidence: 99%

Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis Is Inhibited by Bcl-2 but Restored by the Small Molecule Bcl-2 Inhibitor, HA 14-1, in Human Colon Cancer Cells

Sinicrope

Penington

Tang

2004

Clinical Cancer Research

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Purpose: Tumor necrosis factor-related apoptosisinducing ligand (TRAIL) is a promising anticancer agent that induces apoptosis in multiple tumor cell types while sparing most normal cells. We determined the effect of ectopic Bcl-2 expression on TRAIL-induced apoptosis and whether the small molecule Bcl-2 inhibitor, HA14-1, could increase TRAIL sensitivity. Conclusions: Bcl-2 confers apoptosis resistance to TRAIL by inhibiting a mitochondrial amplification step and by inactivating downstream XIAP in SW480 cells. HA14-1 reversed Bcl-2-mediated TRAIL resistance, suggesting a novel strategy for increasing TRAIL sensitivity in Bcl-2-overexpressing colon cancers.

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Failure of Bcl-2 to block mitochondrial dysfunction during TRAIL-induced apoptosis. Tumor necrosis-related apoptosis-inducing ligand.

Cited by 30 publications

References 0 publications

Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

GDNF Protects against Aluminum-Induced Apoptosis in Rabbits by Upregulating Bcl-2 and Bcl-XL and Inhibiting Mitochondrial Bax Translocation

Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis Is Inhibited by Bcl-2 but Restored by the Small Molecule Bcl-2 Inhibitor, HA 14-1, in Human Colon Cancer Cells

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