The Phosphatidylinositol 3-Kinase (PI3K)-Akt Pathway Suppresses Bax Translocation to Mitochondria

Tsuruta, Fuminori; Masuyama, Norihisa; Gotoh, Yukiko

doi:10.1074/jbc.m108975200

Cited by 333 publications

(219 citation statements)

References 50 publications

(44 reference statements)

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“…Such a supposition is further supported by the finding that the inhibition of PI3-K does not trigger apoptosis in PC12 cells. 6 Activation of the PI3-K/Akt pathway has been shown to prevent apoptosis associated with the translocation of Bax and the release of cytochrome c. 31,32 In contrast, downregulation of the PI3-K pathway was shown to induce both the translocation of Bax and apoptosis. 32 Inactivation of Akt by peroxynitrite may result in decreased phosphorylation of its downstream target Bad.…”

Section: Discussionmentioning

confidence: 99%

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

et al. 2006

Cell Death Differ

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The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death. Peroxynitrite-induced death was prevented by overexpression of Bcl-2 and by cyclosporin A, implicating the involvement of the intrinsic apoptotic pathway. Selective inhibition of mixed lineage kinase (MLK), p38 or JNK does not attenuate the decrease in Akt phosphorylation showing that inactivation of the Akt pathway occurs independently of the MLK/MAPK pathway. Together, these results reveal that peroxynitrite-induced activation of the intrinsic apoptotic pathway involves interactions with the MLK/MAPK and Akt signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

et al. 2006

Cell Death Differ

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“…However, the major effect of E2F1 in conferring numerous survival advantages has been shown to be mediated through the activation of the Akt-signaling pathway (Chaussepied and Ginsberg, 2004;Liu et al, 2006). The activation of Akt was shown to be associated with the inhibition of various proapoptotic effectors and the suppression of Ask1/p38MAPK/JNK-mediated cell death (Kennedy et al, 1997;Zhou et al, 2000;Testa and Bellacosa, 2001;Tsuruta et al, 2002). In this study, we showed that miR-330 can significantly decrease the phosphorylation of targeted intracellular kinases (pAkt1, p-Akt2, p-Akt3 and p-GSK-3b) in PC-3 cells (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-330 acts as tumor suppressor and induces apoptosis of prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation

et al. 2009

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MicroRNAs (miRNAs) make up a novel class of gene regulators; they function as oncogenes or tumor suppressors by targeting tumor-suppressor genes or oncogenes. A recent study that analysed a large number of human cancer cell lines showed that miR-330 is a potential tumorsuppressor gene. However, the function and molecular mechanism of miR-330 in determining the aggressiveness of human prostate cancer has not been studied. Here, we show that miR-330 is significantly lower expressed in human prostate cancer cell lines than in nontumorigenic prostate epithelial cells. Bioinformatics analyses reveal a conserved target site for miR-330 in the 3 0 -untranslated region (UTR) of E2F1 at nucleotides 1018-1024. MiR-330 significantly suppressed the activity of a luciferase reporter containing the E2F1-3 0 -UTR in the cells. This activity could be abolished with the transfection of anti-miR-330 or mutated E2F1-3 0 -UTR. In addition, the expression level of miR-330 and E2F1 was inversely correlated in cell lines and prostate cancer specimens. After overexpressing of miR-330 in PC-3 cells, cell growth was suppressed by reducing E2F1-mediated Akt phosphorylation and thereby inducing apoptosis. Collectively, this is the first study to show that E2F1 is negatively regulated by miR-330 and also show that miR-330 induces apoptosis in prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation.

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“…However, as the mitochondrial membrane potential loss and apoptotic cell death induced by the combination treatment are not fully inhibited by p38 MAPK inhibition or Bax-siRNA targeting, it is possible that undefined signals other than p38 MAPK-Bax signaling also play an important role in combination treatment -induced cytochrome c release and subsequent cell death. Recently, The phosphatidylinositol 3-kinase/Akt pathway is known to suppress translocation of Bax to the mitochondria (47). Therefore, we examined if the combination treatment suppresses the phosphatidylinositol 3-kinase/Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

Park¹,

Kang²,

Park

et al. 2007

Molecular Cancer Therapeutics

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Resistance to anticancer drugs can sometimes be overcome by combination treatment with other therapeutic drugs. Here, we showed that phytosphingosine treatment in combination with arsenic trioxide (As 2 O 3 ) enhanced cell death of naturally As 2 O 3 -resistant human myeloid leukemia cells. The combination treatment induced an increase in intracellular reactive oxygen species level, mitochondrial relocalization of Bax, poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cytochrome c release from the mitochondria. N-acetyl-L-cysteine, a thiol-containing antioxidant, completely blocked Bax relocalization, PARP-1 activation, and cytochrome c release. Pretreatment of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, a PARP-1 inhibitor, or PARP-1/small interfering RNA partially attenuated cytochrome c release, whereas the same treatment did not affect Bax relocalization. The combination treatment induced selective activation of p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK by treatment of SB203580 or expression of dominant-negative forms of p38 MAPK suppressed the combination treatment -induced Bax relocalization but did not affect PARP-1 activation. In addition, antioxidant N-acetyl-L-cysteine completely blocked p38 MAPK activation. These results indicate that phytosphingosine in combination with As 2 O 3 induces synergistic apoptosis in As 2 O 3 -resistant leukemia cells through the p38 MAPKmediated mitochondrial translocation of Bax and the PARP-1 activation, and that p38 MAPK and PARP-1 activations are reactive oxygen species dependent. The molecular mechanism that we elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to As 2 O 3 treatment. [Mol Cancer Ther 2007;6(1):82 -92]

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The Phosphatidylinositol 3-Kinase (PI3K)-Akt Pathway Suppresses Bax Translocation to Mitochondria

Cited by 333 publications

References 50 publications

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

MicroRNA-330 acts as tumor suppressor and induces apoptosis of prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

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