Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery

Datta, Sandeep Robert; Dudek, Henryk; Tao, Xu; Masters, Shane C.; Fu, Haian; Gotoh, Yukiko; Greenberg, Michael E.

doi:10.1016/s0092-8674(00)80405-5

Cited by 5,154 publications

(3,962 citation statements)

References 54 publications

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“…Another is dependent on glycogen synthase kinase-3, another substrate of Akt. The alteration of Bcl-2 protein expression via phosphorylation of the pro-apoptotic members of its Bcl-2 protein family, Bad, has also been identified as a key target of Akt cell survival-signaling pathway (Datta et al, 1997;Adams and Cory, 1998).…”

Section: Resultsmentioning

confidence: 99%

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

et al. 2007

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The recent discovery of cancer stem cells (CSCs) has played a pivotal role in changing our view of carcinogenesis and chemotherapy. Based on this concept, CSCs are responsible for the formation and growth of neoplastic tissue and are naturally resistant to chemotherapy, explaining why traditional chemotherapies can initially shrink a tumor but fails to eradicate it in full, allowing eventual recurrence. Recently, we identified a CSC population in hepatocellular carcinoma (HCC) characterized by their CD133 phenotype. However, the molecular mechanism by which it escapes conventional therapies remains unknown. Here, we examined the sensitivity of these cells to chemotherapeutic agents (doxorubicin and fluorouracil) and the possible mechanistic pathway by which resistance may be regulated. Purified CD133 þ HCC cells isolated from human HCC cell line and xenograft mouse models survived chemotherapy in increased proportions relative to most tumor cells which lack the CD133 phenotype; the underlying mechanism of which required the preferential expression of survival proteins involved in the Akt/PKB and Bcl-2 pathway. Treatment of CD133 þ HCC cells with an AKT1 inhibitor, specific to the Akt/PKB pathway, significantly reduced the expression of the survival proteins that was normally expressed endogenously. In addition, treatment of unsorted HCC cells with both anticancer drugs in vitro significantly enriched the CD133 þ subpopulation.In conclusion, our results show that CD133 þ HCC cells contribute to chemoresistance through preferential activation of Akt/PKB and Bcl-2 cell survival response. Targeting of this specific survival signaling pathway in CD133 þ HCC CSCs may provide a novel therapeutic model for the disease.

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Section: Resultsmentioning

confidence: 99%

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

et al. 2007

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“…This is relevant for prostate cancer, where survivin is highly expressed (Fornaro et al, 2003;Krajewska et al, 2003), and Akt activity is commonly deregulated after loss of the inhibitory lipid phosphatase, phosphatase and tensin homolog deleted on chromosome 10 (Majumder and Sellers, 2005). In turn, increased Akt activity provides a broad antiapoptotic environment through cytoplasmic trapping of cell death mediators (Datta et al, 1997;Goswami et al, 2005), modulation of NFkB (Kane et al, 2002(Kane et al, , 1999 and repression of apoptotic inducers (Brunet et al, 1999). In addition, Akt phosphorylates and inactivates the tuberous sclerosis complex, TSC2, a negative regulator of mTOR signaling (Wullschleger et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Regulation of survivin expression by IGF-1/mTOR signaling

et al. 2006

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“…AKT, a key molecule of many receptor tyrosine kinase response pathways that are involved in cell proliferation, migration and inhibition of apoptosis, is also activated under hypoxic/ischemic condition (Chen et al, 2001;Jiang et al, 2002). AKT directly phosphorylates and inhibits proapoptotic factors, such as Bad and caspase-9, and is transiently activated during hypoxia (Datta et al, 1997;Cardone et al, 1998;Romashkova and Makarov, 1999). Moreover, it stimulates the phosphorylation of I kappa B Kinase cells (IKK) or cyclic AMP-responsive elementbinding protein (CREB) to increase the expression of genes promoting cell survival (Du and Montminy, 1998).…”

mentioning

confidence: 99%

Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2

Kim

et al. 2006

Oncogene

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Apaf-1-interacting protein (APIP) was previously isolated as an inhibitor of mitochondrial cell death interacting with Apaf-1. Here, we report a hypoxia-selective antiapoptotic activity of APIP that induces the activation of AKT and extracellular signal-regulated kinase (ERK)1/2. Stable expression of APIP in C2C12 (C2C12/APIP) cells suppressed cell death induced by hypoxia and etoposide. Unlike etoposide, however, APIP induces the sustained activation of AKT and ERK1/2 and the phosphorylation of caspase-9 during hypoxia. Inhibition of AKT and ERK1/2 activation by the treatments with phosphatidylinositol 3 0 -kinase and mitogen-activated protein kinase kinase (MEK)1/2 inhibitors sensitized C2C12/APIP cells to hypoxic cell death and abolished the hypoxia-induced phosphorylation of caspase-9. Further, overexpression of phosphorylation-mimic caspase-9 mutants (caspase-9-T125E and caspase-9-S196D), but not phosphorylation-defective caspase-9 mutants (caspase-9-T125A and caspase-9-S196A), effectively suppressed hypoxia-induced death of C2C12 cells. These results elucidate a novel Apaf-1-independent antiapoptotic activity of APIP during hypoxic cell death, inducing the sustained activation of AKT and ERK1/2 and leading to caspase-9 phosphorylation.

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Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery

Cited by 5,154 publications

References 54 publications

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

Regulation of survivin expression by IGF-1/mTOR signaling

Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2

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