STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells

Bhattacharya, Sujoy; Ray, Ramesh M.; Johnson, Leonard R.

doi:10.1042/bj20050465

Cited by 240 publications

(232 citation statements)

References 39 publications

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“…For example, STAT3 plays an important role in oncogenesis by upregulating the transcription of several genes that control tumor cell survival, resistance to apoptosis, cell cycle progression and angiogenesis. Target genes of STAT3 include Bcl-2 (Bhattacharya et al, 2005), Bcl-X L (Bromberg et al, 1999), c-myc (Kiuchi et al, 1999) and Mcl-1 (Epling-Burnette et al, 2001), and genes encoding cyclin D1 (Bromberg et al, 1999), vascular endothelial growth factor (Niu et al, 2002) and human telomerase reverse transcriptase (Konnikova et al, 2005). It was previously shown in many cancer cell types that when the STAT3 pathway was blocked by AG490, the expression of the STAT3 target genes was downregulated and apoptosis was induced (Meydan et al, 1996;EplingBurnette et al, 2001;Rahaman et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

et al. 2006

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Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC 50 values for WP1066 were 5.6 lM in U87-MG cells and 3.7 lM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-X L and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (Po0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

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Section: Discussionmentioning

confidence: 99%

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

et al. 2006

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“…Recently, several studies have reported that genes involved in cell protection against apoptosis are regulated by STAT signaling (Bhattacharya et al, 2005;Harada et al, 2005;Zhang et al, 2007). Harada et al (2005) reported that in transgenic mice expressing dominant-inhibitory STAT3, Bcl-2 and Bcl-xL upregulation mediated by granulocyte colony-stimulating factor was diminished in cardiomyocytes (Harada et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Preconditioning Mediated by Sublethal Oxygen—Glucose Deprivation-Induced Cyclooxygenase-2 Expression via the Signal Transducers and Activators of Transcription 3 Phosphorylation

Kim

Raval

Pérez-Pinzón

2008

J Cereb Blood Flow Metab

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The signal transducers and activators of transcription (STATs) were found to be essential for cardioprotection. However, their role in preconditioning (PC) neuroprotection remains undefined. Previously, our studies showed that PC mediated a signaling cascade that involves activation of epsilon protein kinase C (ePKC), extracellular signal-regulated kinase (ERK1/2), and cyclooxygenase-2 (COX-2) pathways. However, the intermediate pathway by which ERK1/2 activates COX-2 was not defined. In this study, we investigated whether the PC-induced signaling pathway requires phosphorylation of STAT isoforms for COX-2 expression. To mimic PC or lethal ischemia, mixed cortical neuron/astrocyte cell cultures were subjected to 1 and/or 4 h of oxygen-glucose deprivation (OGD), respectively. The results indicated serine phosphorylation of STAT3 after PC or ePKC activation. Inhibition of either ePKC or ERK1/2 activation abolished PC-induced serine phosphorylation of STAT3. Additionally, inhibition of STAT3 prevented PC-induced COX-2 expression and neuroprotection against OGD. Therefore, our findings suggest that PC signaling cascade involves STAT3 activation after ePKC and ERK1/2 activation. Finally, we show that STAT3 activation mediates COX-2 expression and ischemic tolerance.

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“…cell proliferation was determined using the WSt-1 assay (Dojin Kagaku corp., japan). a 100 µl volume of floating cells (3x10 4 to 1x10 5 /ml) was seeded into each well of a 96-well microculture plate (corning, ny), and 100 µl of various doses of compounds sequentially diluted with DMSO (100-0.1 µM) was added. After 72 h at 37̊C, 10 µl of combined WSt-1 substrate was added to each well and incubated for 3 h at 37̊C.…”

Section: Methodsmentioning

confidence: 99%

Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation

Akiyama¹

2011

Int J Oncol

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Abstract. Signal transducer and activator of transcription (Stat)3, a member of a family of Dna-binding molecules mediating numerous physiological and oncogenic signaling pathways, is a novel target in cancer cells which show high phosphorylation of STAT3. Recently, we identified a novel small-molecule inhibitor of Stat3 dimerization, StX-0119, as a cancer therapeutic. We investigated the mechanisms responsible for the antitumor activity in vitro and in vivo through numerous biochemical and biological assays. Specifically, the effects of StX-0119 on target genes (c-myc, cyclin D1, survivin) and apoptosis induction were analyzed in tumors treated with StX-0119 in vivo. StX-0119 showed strong growth-inhibitory activity against a broad range of hematological cancer cell lines, particularly lymphomas. StX-0119 suppressed the growth of Scc3 cells, a human lymphoma cell line with highly activated Stat3, through apoptosis and down-regulation of Stat3 targets such as c-myc, cyclin D1, survivin and Bcl-xl. notably, tyr-705-phosphorylated Stat3 up-regulation was not significantly suppressed by STX-0119, as opposed to other Stat3 inhibitors. StX-0119 demonstrated potent antitumor effects in vivo in Scc3-bearing nude mice by way of the down-regulation of Stat3 target genes and induction of apoptosis in the tumors. thus, StX-0119 may be a new type of Stat3 inhibitor exhibiting strong antitumor activity. Introductionthe signal transducer and activator of transcription (Stat) protein family is a group of transcription factors that play an important role in relaying signals from growth factors and cytokines (1-3). Stat3 is reported to be involved in oncogenesis by up-regulating the transcription of several genes that control tumor cell survival, resistance to apoptosis, cell cycle progression and angiogenesis. targets of Stat3 include Bcl-2 (4), Bcl-xl (5), c-myc (6), cyclin D1 (7), vascular endothelial growth factor (8) and human telomerase reverse transcriptase (9).Several Stats have been associated with the proliferation and survival of cancer cells; however Stat3 is also widely expressed in normal cells. generally, Stat3 is temporarily activated in a manner strictly regulated by the protein inhibitor of Stats (PiaS), Src homology (SH)2-containing tyrosine phosphatases (SHP1 and SHP2) (10), and suppressor of cytokine signaling/extracellular signal-regulated kinase (SOCS/ERK) (11) to protect cells from excess inflammatory signaling.Moreover, persistent activation of Stat3 occurs in many hematological malignancies (12,13) and solid cancers. constitutive Stat3 activation up-regulates the expression of anti-apoptotic factors including Bcl-xl, Bcl-2 and Mcl-1 and promotes the survival of tumor cells, thus contributing to resistance to faS-or chemotherapy-induced apoptosis (14). Blocking of STAT3 signaling demonstrated significant growth inhibition of cancer cells by down-regulation of the expression of anti-apoptotic genes, leading to apoptosis. the activation of Stat3 occurs when it is phosphorylated at the tyr-705 residue. this...

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STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells

Cited by 240 publications

References 39 publications

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

Preconditioning Mediated by Sublethal Oxygen—Glucose Deprivation-Induced Cyclooxygenase-2 Expression via the Signal Transducers and Activators of Transcription 3 Phosphorylation

Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation

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