Akt/Protein Kinase B Signaling Inhibitor-2, a Selective Small Molecule Inhibitor of Akt Signaling with Antitumor Activity in Cancer Cells Overexpressing Akt

Yang, Lin; Han, Dong; Sun, Mei; Liu, Qiyuan; Sun, Xia; Feldman, Richard I.; Hamilton, Andrew D.; Polokoff, Mark A.; Nicosia, Santo V.; Herlyn, Meenhard; Sebti, Saı̈d M.; Cheng, Jin Q.

doi:10.1158/0008-5472.can-04-0343

Cited by 406 publications

(355 citation statements)

References 13 publications

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“…We therefore exposed NGF-treated PC12 cells to two drugs (Triciribine and 3-formylchromone thiosemicarbazone, Cu(II)Cl 2 complex) that inhibit Akt phosphorylation by different mechanisms. 43,44 Concentrations that blocked Akt phosphorylation (Figure 8d) caused death at levels similar to those with NGF deprivation (Figure 8e) and significantly induced Trib3 transcripts ( Figure 8f). As a positive control, we also detected induction of Bim transcripts.…”

Section: Ngf Deprivation Induces Trib3 Mrna and Proteinmentioning

confidence: 72%

A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons

2013

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The mechanisms governing neuron death following NGF deprivation are incompletely understood. Here, we show that Trib3, a protein induced by NGF withdrawal, has a key role in such death via a loop involving the survival kinase Akt and FoxO transcription factors. Trib3 overexpression is sufficient to induce neuron death, and silencing of endogenous Trib3 strongly protects from death when NGF is withdrawn. Mechanism studies reveal that Trib3 interferes with phosphorylation/activity of Akt and contributes to Akt inactivation after NGF deprivation. FoxO1a, a direct Akt substrate, is dephosphorylated upon NGF withdrawal and consequently undergoes nuclear translocation and activates pro-apoptotic genes. We find that Trib3 is required for FoxO1a dephosphorylation and nuclear translocation after NGF deprivation. Conversely, Trib3 induction requires FoxO transcription factors, which show enhanced occupancy of the Trib3 promoter region following NGF withdrawal. Collectively, these findings support a mechanism in which NGF deprivation, Akt dephosphorylation/inactivation, FoxO dephosphorylation/ activation and Trib3 induction are linked in a self-amplifying feed-forward loop that culminates in neuron death.

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Section: Ngf Deprivation Induces Trib3 Mrna and Proteinmentioning

confidence: 72%

A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons

2013

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“…To demonstrate whether the protective effect of LIF is mediated through Akt activation we used triciribine (Akt inhibitor V), reported to block Akt activation without inhibiting PI3K or PDK-1. 29 The ability of inhibitor V to block Akt activation was first confirmed by measuring LIF-induced phosphorylation of the T308 and S473 sites on Akt, as shown in Figure 1c. Inhibitor V and the PI3K inhibitor LY 294002 (LY) were determined to block the protective effects of LIF on H 2 0 2 -induced mitochondrial depolarization (Figure 1b).…”

Section: Resultsmentioning

confidence: 92%

Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II

2007

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Akt activation supports survival of cardiomyocytes against ischemia/reperfusion, which induces cell death through opening of the mitochondrial permeability transition pore (PT-pore). Mitochondrial depolarization induced by treatment of cardiomyocytes with H 2 0 2 is prevented by activation of Akt with leukemia inhibitory factor (LIF). This protective effect is observed even when cardiomyocytes treated with LIF are permeabilized and mitochondrial depolarization is elicited by elevating Ca 2 þ . Cell fractionation studies demonstrate that LIF treatment increases both total and phosphorylated Akt in the mitochondrial fraction. Furthermore, the association of Akt with HK-II is increased by LIF. HK-II contains consensus sequences for phosphorylation by Akt and LIF treatment induces PI3K-and Akt-dependent HK-II phosphorylation. Addition of recombinant kinase-active Akt to isolated adult mouse heart mitochondria stimulates phosphorylation of HK-II and concomitantly inhibits the ability of Ca 2 þ to induce cytochrome c release. This protection is prevented when HK-II is dissociated from mitochondria by incubation with glucose 6-phosphate or HK-II-dissociating peptide. Finally LIF increases HK-II association with mitochondria and dissociation of HK-II from mitochondria attenuates the protective effect of LIF on H 2 0 2 -induced mitochondrial depolarization in cardiomyocytes. We conclude that Akt has a direct effect at the level of the mitochondrion, which is mediated via phosphorylation of HK-II and results in protection of mitochondria against oxidant or Ca 2 þ -stimulated PT-pore opening.

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“…Mice were injected i.p. with the Rapamycin 37 (Sigma-Aldrich, St. Louis, MO, USA, #R0395) 7.5 mg per kg of body weight in 5% DMSO or AKT inhibitor 38 (NSC 154020, Calbiochem, Millipore) 20 mg per kg of body weight in 5% DMSO or ATM inhibitor (KU55933, Calbiochem, Millipore) 15 mg per kg of body weight in 5% DMSO or DNA-PK inhibitor 39 (NU7026, Sigma-Aldrich) 15 mg per kg of body weight in 5% DMSO or p38MAPK inhibitor 12 (SB202190, SigmaAldrich) 10 mg per kg of body weight in 5% DMSO, or GSK-3 inhibitors IX 6 (Calbiochem, Millipore) 15 mg per kg of body weight in 5% DMSO. After 6, 10, or 12 h, mice were euthanized and organs were collected for subsequent analysis.…”

Section: Methodsmentioning

confidence: 99%

Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis

et al. 2012

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Conversion of intestinal stem cells into tumor-initiating cells is an early step in Apc Min -induced polyposis. Wild-type p53-induced phosphatase 1 (Wip1)-dependent activation of a DNA damage response and p53 has a permanent role in suppression of stem cell conversion, and deletion of Wip1 lowers the tumor burden in Apc Min mice. Here we show that cyclin-dependent kinase inhibitor 2a, checkpoint kinase 2, and growth arrest and DNA damage gene 45a (Gadd45a) exert critical functions in the tumor-resistant phenotype of Wip1-deficient mice. We further identified Gadd45a as a haploinsufficient gene in the regulation of Wip1-dependent tumor resistance in mice. Gadd45a appears to function through its ability to activate the Jnk-dependent signaling pathway that in turn is a necessary mediator of the proapoptotic functions of p53 that respond to activation of the b-catenin signaling pathway. We propose that silencing of Gadd45a is sufficient to override p53 activation in the presence of active b-catenin under conditions of an enhanced DNA damage response. Cell Death and Differentiation (2012) 19, 1761-1768 doi:10.1038/cdd.2012; published online 4 May 2012Conversion of normal cells into tumor-initiating cells is an initial step in the course of formation of any tumor. 1 The majority of cells in an organism are terminally differentiated and thus are not capable of conversion into tumor-initiating cells, which requires cellular proliferation. In many instances, proliferative progenitors are programmed to divide only a few times before full differentiation; acquiring oncogenic mutations at this stage may also have a limited impact on tumorigenesis unless the mutation blocks differentiation. Increasing evidence in turn indicates that certain types of cancers originate from adult stem cells, the only proliferative cells that exist in the animal for a significant period of time that may be sufficient to accumulate oncogenic mutations. Several studies have demonstrated the role of adult stem cells as an origin of cancer, at least in certain tissues such as mouse intestine. 2 Stem cell-specific inactivation of Apc (adenomatous polyposis coli ), the major regulator of tumorigenesis in the intestine, results in full-blown polyposis within a few weeks. 3 In contrast, deletion of Apc in proliferative progenitors or more differentiated cell types fails to induce sustainable cancer. 3 In many instances, activation of oncogenes in normal cells sets off the defense mechanisms to protect them from potential transformation. 4 The major pathway that has had evolved to perform this function is controlled by a tumor suppressor p53. Depending on the strength of the signal, which in many cases relies on the type of oncogene, p53 activates apoptosis, transient or permanent cell cycle arrest called senescence. 5 Modulation of p53 levels and activity may therefore be critical to the regulation of cell susceptibility to oncogenic transformation. Regulation of p53 by various means to prevent oncogenic transformation may be especially important when ...

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Akt/Protein Kinase B Signaling Inhibitor-2, a Selective Small Molecule Inhibitor of Akt Signaling with Antitumor Activity in Cancer Cells Overexpressing Akt

Cited by 406 publications

References 13 publications

A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons

A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons

Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II

Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis

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