AKT activation and response to interferon-β in human cancer cells

Lei, Hanqin; Furlong, Patrick J.; Hee, J. Kyung; Mullins, C. Daniel; Cantor, Robert S.; Fraker, Douglas L.; Spitz, Francis R.

doi:10.4161/cbt.4.7.1767

Cited by 21 publications

(16 citation statements)

References 37 publications

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“…For instance, previous studies have shown that Akt activation in certain colorectal cell lines leads to phosphorylation of Bad and resistance to IFNβ-induced apoptosis. 63 In addition, Akt may be a mediator of pro-survival signals induced by IFNβ in primary astrocytes. 64 This is particularly interesting as such enhanced survival of astrocytes may be a mechanism by which IFNβ exhibits its beneficial effects in multiple sclerosis.…”

Section: Functional Consequences Of Akt-controlled Mrna Translation Omentioning

confidence: 99%

Akt and mRNA translation by interferons

Kaur¹,

Katsoulidis²,

Platanias³

2008

Cell Cycle

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Section: Functional Consequences Of Akt-controlled Mrna Translation Omentioning

confidence: 99%

Akt and mRNA translation by interferons

Kaur¹,

Katsoulidis²,

Platanias³

2008

Cell Cycle

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“…Furthermore, the ectopic expression of AKT induces cell survival and malignant transformation, whereas the inhibition of AKT activity stimulates apoptosis in a range of mammalian cells (10,12,(14)(15)(16)(17). Recent studies have identified the substrates of AKT that are involved in the pro-cell survival effects, which thus far include glycogen synthase kinase-3, mTOR, FKHR, MDM2, p21, HIF-1, IKK, Bad, and caspase-9 (13,(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer

Shankar

Srivastava²

2007

Int J Oncol

132

141

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Abstract. Curcumin (diferulolylmethane), an active ingredient derived from the rhizome of the plant Curcuma longa, has anticancer activity in vitro and in vivo. Although curcumin possesses chemopreventive properties against several types of cancer, the molecular mechanisms by which it inhibits cell growth and induces apoptosis are not clearly understood. Our data revealed that curcumin inhibited growth and induced apoptosis in androgen-dependent and -independent prostate cancer cells, but had no effect on normal human prostate epithelial cells. Curcumin downregulated the expression of Bcl-2, and Bcl-X L and upregulated the expression of p53, Bax, Bak, PUMA, Noxa, and Bim. Curcumin upregulated the expression of p53 as well as its phosphorylation at serine 15, and acetylation in a concentration-dependent manner. Acetylation of histone H3 and H4 was increased in cells treated with curcumin, suggesting histone modification may regulate gene expression. Treatment of LNCaP cells with curcumin resulted in translocation of Bax and p53 to mitochondria, production of reactive oxygen species, drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and induction of apoptosis. Furthermore, curcumin inhibited expression of phosphatidylinositol-3 kinase (PI3K) p110 and p85 subunits, and phosphorylation of Ser 473 AKT/PKB. Downregulation of AKT by inhibitors of PI3K (Wortmannin and LY294002) and AKT, or by dominant negative AKT increased curcumininduced apoptosis, whereas transfection of constitutively active AKT attenuated this effect. Similarly, wild-type phosphatase and tensin homolog deleted from chromosome 10 (PTEN) enhanced curcumin-induced apoptosis and, in contrast, inactive PTEN (G129E and G129R) inhibited curcumin-induced apoptosis. Overexpression of constitutively active AKT inhibited curcumin-induced p53 translocation to mitochondria, and Smac release to cytoplasm, whereas inhibition of AKT by dominant negative AKT enhanced curcumin-induced p53 translocation to mitochondria and Smac release. Our study establishes a role for AKT in modulating the direct action of p53 on the caspasedependent mitochondrial death pathway and suggests that these important biological molecules interact at the level of the mitochondria to influence curcumin sensitivity. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.

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“…It has also been reported that STAT1-independent signaling, such as the PI3K/Akt-signaling pathway, is implicated in the resistance to IFNs (20,54). Previous studies demonstrated that sensitivity and resistance to IFN␤ in colorectal cancer cells depends on the status of Akt activation after IFN␤ treatment (20). In IFN␤-resistant colorectal cancer cells, treatment with IFN␤ up-regulated the activation of Akt, which induced downstream anti-apoptotic pathways (20).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies demonstrated that sensitivity and resistance to IFN␤ in colorectal cancer cells depends on the status of Akt activation after IFN␤ treatment (20). In IFN␤-resistant colorectal cancer cells, treatment with IFN␤ up-regulated the activation of Akt, which induced downstream anti-apoptotic pathways (20). In contrast to the positive regulatory role of the PI3K/Akt pathway, IFN␥-induced apoptosis and growth inhibition have been shown to be associated with a persistent suppression of the constitutive tyrosine-phosphorylated STAT3.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, reduced expression of ISGF-3 (a tetramer complex with STAT1, STAT2, and IRF-9) has been detected in skin squamous carcinoma cells from surgical specimens (18). However, some types of tumor cells have been reported to resist IFNs despite having a normal JAK-STAT pathway (7,12,19,20). Thus, both JAK-STAT-dependent and-independent mechanisms appear to explain IFN resistance.…”

Section: Interferon-␥ (Ifn␥)mentioning

confidence: 99%

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