Preferential Inhibition of Akt and Killing of Akt-Dependent Cancer Cells by Rationally Designed Phosphatidylinositol Ether Lipid Analogues

Castillo, S. Sianna; Brognard, John; Petukhov, Pavel A.; Zhang, Chunyu; Tsurutani, Junji; Granville, Courtney A.; Li, Min; Jung, Michael; West, Kip A.; Gills, Joell G.; Kozikowski, Alan P.; Dennis, Phillip A.

doi:10.1158/0008-5472.can-03-1530

Cited by 115 publications

(100 citation statements)

References 67 publications

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“…AI-III is a 2-modified, 3-deoxy phosphatidylinositol analog with phosphate linkers, which specifically inhibits Akt phosphorylation and activity without affecting any upstream kinases such as PI3K or PDK-1 as well as extracellular signalregulated kinase (ERK). 27,28 Effect of Akt inhibition on cell viability and apoptotic cell death Both LY and AI-III blocked Akt activation in a dose-dependent manner as measured by Akt enzymatic activity ( Figure 1a) and level of phosphorylated Akt (Figure 1b). Additionally, AI-III did not have any effect on PI3 kinase activity (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Akt inhibition upregulates FasL, downregulates c-FLIPs and induces caspase-8-dependent cell death in Jurkat T lymphocytes

Uriarte¹,

Joshi‐Barve²,

Song³

et al. 2005

Cell Death Differ

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In T lymphocytes, the role of Akt in regulating Fas/Fas ligand (FasL)-mediated apoptotic signaling and death is not clearly understood. In this study, we observed that inhibition of Akt causes enhanced expression of FasL mRNA and protein and increased death-inducing signaling complex (DISC) formation with Fas-associated death domain (FADD) and procaspase-8 recruitment. Also, caspase-8 was activated at the DISC with accompanying decrease in c-FLIP s expression. FasL neutralizing antibody significantly decreased apoptotic death in the Akt-inhibited T cells. Additionally, Akt inhibition-induced Fas signaling was observed to link to the mitochondrial pathway via Bid cleavage. Further, inhibition of caspase-8 activity effectively blocked the loss of mitochondrial membrane potential and DNA fragmentation, suggesting that DISC formation and subsequent caspase-8 activation are critical initiating events in Akt inhibition-induced apoptotic death in T lymphocytes. These data demonstrate yet another important survival function governed by Akt kinase in T lymphocytes, which involves the regulation of FasL expression and consequent apoptotic signaling.

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Section: Resultsmentioning

confidence: 99%

Akt inhibition upregulates FasL, downregulates c-FLIPs and induces caspase-8-dependent cell death in Jurkat T lymphocytes

Uriarte¹,

Joshi‐Barve²,

Song³

et al. 2005

Cell Death Differ

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“…Furthermore, many of the commonly used cytostatic drugs activate Akt in cancer cells (20). Therefore, Akt is an attractive target for cancer therapy (21,22). Statins, which are well-characterized and established pharmaceuticals, may thus represent a potentially new and safe class of inhibitors of Akt signaling.…”

Section: Introductionmentioning

confidence: 99%

Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs

Roudier

Mistafa

Stenius

2006

Molecular Cancer Therapeutics

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Cholesterol-lowering statins have been shown to have anticancer effects in different models and sensitize human tumor cells to cytostatic drugs. We have investigated the effect of statins on Akt/protein kinase B signaling and the sensitizing effect of cytostatic drugs. It was found that insulin -and cytostatic drug -induced Akt phosphorylation and nuclear translocation was inhibited by pravastatin and atorvastatin in HepG2, A549, and H1299 cells in an mTOR-dependent manner. Statins also induced mTORdependent phosphorylation of insulin receptor substrate 1. In p53 wild-type cells (HepG2 and A549), pretreatment with statins did not sensitize cells to etoposide in concentrations which induced p53 stabilization. In line with our previous data, statins were found to attenuate the etoposide-induced p53 response. However, silencing p53 by RNA interference rescued the sensitizing effect. We also show that in a p53-deficient cell line (H1299), pretreatment with atorvastatin sensitized cells to etoposide, doxorubicin, and 5-fluorouracil and increased the level of apoptosis. Taken together, these data suggest that a mTOR-dependent, statin-induced inhibition of Akt phosphorylation and nuclear translocation sensitizes cells to cytostatic drugs. However, this effect can be counteracted in p53 competent cells by the ability of statins to destabilize p53. [Mol Cancer Ther 2006;5(11):2706 -15]

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“…Phosphatidylinositol ether lipid analogues (PIA) are analogues of the products of phosphatidylinositol 3-kinase (PI3K) that were designed to target the pleckstrin homology domain of Akt (1). PIAs inhibit Akt translocation, phosphorylation, and kinase activity and preferentially induce apoptosis in breast and lung cancer cell lines with high levels of active Akt (2). A second Akt-independent activity of PIAs has recently been identified: activation of the proapoptotic stress kinase p38a.…”

Section: Introductionmentioning

confidence: 99%

Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt

Gills¹,

Holbeck

Hollingshead

et al. 2006

Molecular Cancer Therapeutics

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The serine/threonine kinase Akt is a promising target in cancer. We previously identified five phosphatidylinositol ether lipid analogues (PIA) that inhibited Akt activation and selectively killed lung and breast cancer cells with high levels of Akt activity. To assess the spectrum of activity in other cell types and to compare PIAs with other inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, we compared growth inhibition by PIAs against the PI3K inhibitors LY294002 and wortmannin and the mTOR inhibitor rapamycin in the NCI60 cell line panel.

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Preferential Inhibition of Akt and Killing of Akt-Dependent Cancer Cells by Rationally Designed Phosphatidylinositol Ether Lipid Analogues

Abstract: ABSTRACT

Cited by 115 publications

References 67 publications

Akt inhibition upregulates FasL, downregulates c-FLIPs and induces caspase-8-dependent cell death in Jurkat T lymphocytes

Akt inhibition upregulates FasL, downregulates c-FLIPs and induces caspase-8-dependent cell death in Jurkat T lymphocytes

Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs

Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt

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