The involvement of PI 3-K/Akt-dependent up-regulation of Mcl-1 in the prevention of apoptosis of Hep3B cells by interleukin-6

Kuo, Min-Liang; Chuang, Shuang‐En; Lin, Jaw–Town; Yang, Sen‐Yeu

doi:10.1038/sj.onc.1204140

Cited by 135 publications

(115 citation statements)

References 47 publications

(43 reference statements)

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“…Depression of Mcl-1 induction using Mcl-1 antisense oligonucleotide promoted PMA-mediated apoptosis in U937 cells (43). In Hep3B hepatocytes, Mcl-1 is up-regulated by the PI3K/Akt pathway and inhibits apoptosis induced by TGF-␤ (44). In the present study, it was demonstrated that TNF-␣ induced Mcl-1 expression via PI3K/Akt.…”

Section: Discussionsupporting

confidence: 49%

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Osawa

Nagaki

Banno

et al. 2003

The Journal of Immunology

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Using a cDNA microarray analysis, we identified x-ray-inducible immediate early response factor-1 (IEX-1) as a proapoptotic gene which was induced by TNF-α and also depend on NF-κB activation in Hc human hepatocytes. In these cells only the original form of IEX-1, termed IEX-1S, but not its longer transcript IEX-1L, was expressed. Overexpression of IEX-1S resulted in promotion of TNF-α-induced apoptosis in Hc cells expressing a mutant form of IκB. This proapoptotic action can be explained by its inhibitory findings on survival signals; inhibition of TNF-α-induced activation and expression of phosphatidylinositol 3-kinase (PI3K)/Akt, and also blockage of expression of Mcl-1, an antiapoptotic Bcl-2 family member which is located downstream of Akt, was inhibited by IEX-1S. LY 294002, an inhibitor of PI3K, increased IEX-1S expression induced by TNF-α and accelerated TNF-α-induced apoptosis in IκB-treated Hc cells. Overexpression of the dominant-negative Akt enhanced, but the constitutively active Akt suppressed, TNF-α-induced IEX-1S expression, suggesting that PI3K/Akt negatively regulated IEX-1S expression. These results demonstrate that NF-κB-dependent recruitment of IEX-1S may play a proapoptotic role in TNF-α-stimulated hepatocytes through blockage of the PI3K/Akt pathway. Moreover, the reciprocal cross-talk between IEX-1S and PI3K/Akt may closely be involved in the regulation of TNF-α-induced hepatocyte apoptosis.

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Section: Discussionsupporting

confidence: 49%

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Osawa

Nagaki

Banno

et al. 2003

The Journal of Immunology

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“…Of these, inhibitor studies have identified the PI3-kinase and the p38 MAPK pathway as being involved in cell survival signaling in cholangiocytes. IL-6 induced PI 3 kinase signaling resulting in activation of Mcl-1 have been reported in several different settings (39,41,49,51). In contrast, the role of p38 MAPK in mediating Mcl-1 expression has not previously been reported to the best of our knowledge.…”

Section: Discussionmentioning

confidence: 88%

Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes

Meng¹,

Yamagiwa²,

Ueno³

et al. 2006

Journal of Hepatology

115

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“…Protein expression of caspase-8, -9, -3, Bid and GAPDH was assessed by western blotting (c). (Kuo et al, 2001), as well as increased degradation of Mcl-1 via GSK3b or via Noxa (Willis et al, 2005;Maurer et al, 2006;Warr and Shore, 2008). PI103 may increase Bim EL and Noxa levels via FKHRL1, which is negatively regulated by Akt (Dijkers et al, 2000) and transcriptionally stimulates Bim and Noxa (Dijkers et al, 2000;Obexer et al, 2007), and/or by preventing the Akt-dependent phosphorylation of Bim EL , which enhances its proteasomal degradation (Qi et al, 2006).…”

mentioning

confidence: 99%

PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis

et al. 2010

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We recently identified activation of phosphatidylinositol 3 0 -kinase (PI3K)/Akt as a novel predictor of poor outcome in neuroblastoma. Here, we investigated the effect of smallmolecule PI3K inhibitors on chemosensitivity. We provide first evidence that PI3K inhibitors, for example PI103, synergize with various chemotherapeutics (Doxorubicin, Etoposide, Topotecan, Cisplatin, Vincristine and Taxol) to trigger apoptosis in neuroblastoma cells (combination index: high synergy). Mechanistic studies reveal that PI103 cooperates with Doxorubicin to reduce Mcl-1 expression and Bim EL phosphorylation and to upregulate Noxa and Bim EL levels. This shifted ratio of pro-and antiapoptotic Bcl-2 proteins results in increased Bax/Bak conformational change, loss of mitochondrial membrane potential, cytochrome c release, caspase activation and caspase-dependent apoptosis. Although Mcl-1 knockdown enhances Doxorubicin-and PI103-induced apoptosis, silencing of Noxa, Bax/ Bak or p53 reduces apoptosis, underscoring the functional relevance of the Doxorubicin-and PI103-mediated modulation of these proteins for chemosensitization. Bcl-2 overexpression inhibits Bax activation, mitochondrial perturbations, cleavage of caspases and Bid, and apoptosis, confirming the central role of the mitochondrial pathway for chemosensitization. Interestingly, the broad-range caspase inhibitor zVAD.fmk does not interfere with Bax activation or mitochondrial outer membrane permeabilization, whereas it blocks caspase activation and apoptosis, thus placing mitochondrial events upstream of caspase activation. Importantly, PI103 and Doxorubicin cooperate to induce apoptosis and to suppress tumor growth in patients' derived primary neuroblastoma cells and in an in vivo neuroblastoma model, underlining the clinical relevance of the results. Thus, targeting PI3K presents a novel and promising strategy to sensitize neuroblastoma cells for chemotherapy-induced apoptosis, which has important implications for the development of targeted therapies for neuroblastoma.

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The involvement of PI 3-K/Akt-dependent up-regulation of Mcl-1 in the prevention of apoptosis of Hep3B cells by interleukin-6

Cited by 135 publications

References 47 publications

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes

PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis

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