STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells

Hazan‐Halevy, Inbal; Harris, David; Liu, Zhiming; Liu, Jie; Li, Ping; Chen, Xiaomin; Shanker, Sreejesh; Ferrajoli, Alessandra; Keating, Michael J.; Estrov, Zeev

doi:10.1182/blood-2009-10-230060

Cited by 180 publications

(279 citation statements)

References 52 publications

Supporting

Mentioning

264

Contrasting

Order By: Relevance

“…However, other investigators suggested that STAT3 serine phosphorylation is associated with increased nuclear translocation and serves to maximize transcriptional activity (6,64). Hazan-Halevy et al reported that constitutive phosphorylation of STAT3 on Ser727 residues is a critical event in chronic lymphocytic leukemia (CLL) and may serve as a potent therapeutic target (64).…”

Section: Discussionmentioning

confidence: 99%

Erk1/2 activation and modulation of STAT3 signaling in oral cancer

et al. 2014

View full text Add to dashboard Cite

Abstract. Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway possesses confirmed oncogenic potential in oral squamous cell carcinoma (OSCC). Crosstalk with other molecular pathways contributes to STAT3 regulation in cancer. The effects of mitogen-activated protein kinases (MAPKs) and particularly extracellular signal-regulated kinase 1/2 (Erk1/2) on STAT3 signaling in OSCC have not been thoroughly investigated. The present study examined the effects of Erk1/2 modulation on STAT3 signaling and cell growth in OSCC cells. Constitutive expression levels of phosphorylated (tyrosine and serine) and total STAT3, Erk1/2 and cyclin D1 were assessed in OSCC cell lines. Erk1/2 modulation was achieved by pharmacological agents; siRNA silencing against Erk1/2 was also performed. Cell proliferation and viability were assessed. Erk1/2 inhibition with either U0126 treatment or specific siRNA silencing resulted in decreases in p-ser STAT3 and cyclin D1 levels and increases in p-tyr STAT3 in OSCC cells. Moreover, Erk1/2 inhibition resulted in a dose-dependent reduction in OSCC cell growth and viability. Erk1/2 induction had the opposite effects. Taken together, these results are supportive of an active crosstalk between the oncogenic Erk1/2 and STAT3 pathways in OSCC, the significance of which requires further investigation.

show abstract

Section: Discussionmentioning

confidence: 99%

Erk1/2 activation and modulation of STAT3 signaling in oral cancer

et al. 2014

View full text Add to dashboard Cite

show abstract

“…To further investigate the molecular events that determine the effect of dinaciclib on CLL cell survival, we measured the activation status of multiple pro-survival oncogenic signalling pathways that have been reported to be upregulated in B cell malignancies, such as STAT3, NF-κB, p38, PI3K/AKT and RAF/MEK/ERK (Cuní, et al 2004, Hazan-Halevy, et al 2010, Kawauchi, et al 2002, Ogasawara, et al 2003, Pickering, et al 2007, Ringshausen, et al 2002, Rozovski, et al 2014, Sainz-Perez, et al 2006. The phosphorylation level of STAT3 (Tyr705), IκBα (Ser32/36), p38 (Thr180/Tyr182), AKT (Ser473) and ERK (Thr202/Tyr204) were assessed as markers of activation of these pathways in MEC-1.…”

Section: Dinaciclib Inhibits Pro-survival Signals In Cll Cellsmentioning

confidence: 99%

“…NF-κB RelA/p65 activation correlates chemoresistance and poorer clinical outcome in CLL (Cuní, et al 2004, Furman, et al 2000. Moreover, NF-κB activation can be regulated by STAT3 (Liu, et al 2011), which is constitutively phosphorylated at serine 727 in CLL cells (Hazan-Halevy, et al 2010, Rozovski, et al 2014.…”

Section: Introductionmentioning

confidence: 99%

“…Once engaged, it activates pro-survival signals such as the RAF/MEK/ERK, PI3K/AKT, p38, NF-κB and STAT3 pathways, which play a pathogenic role in CLL (Cuní, et al 2004, Hazan-Halevy, et al 2010, Kawauchi, et al 2002, Ogasawara, et al 2003, Pickering, et al 2007, Ringshausen, et al 2002, Rozovski, et al 2014, Sainz-Perez, et al 2006. Nearly half of CLL cases have high levels of constitutively phosphorylated ERK1/2 (Muzio, et al 2008) and in freshly isolated CLL cells, phosphorylated p38 is predominately activated (Sainz-Perez, et al 2006).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

et al. 2016

View full text Add to dashboard Cite

Short title: Effects of Dinaciclib on pro-survival signals in CLL. 2 SUMMARYDinaciclib is a cyclin-dependent kinase inhibitor with clinical potential in different cancers, including Chronic Lymphocytic Leukemia (CLL). In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of CLL cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or IGVH mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated CLL cells, such as STAT3, NF-κB and p38. Also, PI3K/AKT and RAF/MEK/ERK pathways showed a transient and early activation, followed by a later, permanent inhibition. Dinaciclib was also able to block the expression of anti-apoptotic proteins of the BCL-2 family such as MCL-1 and BCL-xL. Finally, we show that low concentrations of dinaciclib enhanced cell sensitivity to ibrutinib and BCL-2 inhibitor ABT-199, two drugs with known effects on CLL. Taken together, our data show that dinaciclib targets multiple pro-survival signalling pathways in CLL, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of CDK inhibitors in CLL in combination with other relevant targeted therapies.

show abstract

“…We next studied AKT isoform activation in the context of the oncogene STAT3 , a factor of clinical significance to CLL, which has been described to directly interact with the AKT1 promoter (Park et al , 2005; Hazan‐Halevy et al , 2010). Activation of CLL cells by T cells resulted in pronounced STAT3 signalling (pY(705)‐STAT3), which could be antagonised by treatment with the STAT3 inhibitor S3I‐201 (Fig 2C).…”

mentioning

confidence: 99%