STAT3 as a therapeutic target in head and neck cancer

Leeman, Rebecca J; Lui, Vivian Wai Yan; Grandis, Jennifer R.

doi:10.1517/14712598.6.3.231

Cited by 204 publications

(168 citation statements)

References 114 publications

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“…A number of findings indicate that STAT3 is constitutively activated and participates in the regulation of cell proliferation, differentiation and apoptosis in HNSCC (17,18). Aberrant STAT3 activation, manifested by increases in STAT3 tyrosine phosphorylation, is considered as a potent promoter of HNSCC initiation and progression, thereby inhibition of STAT3 has been identified as a potential therapeutic target for the treatment of HNSCC (16,18,62).…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant STAT3 activation, manifested by increases in STAT3 tyrosine phosphorylation, is considered as a potent promoter of HNSCC initiation and progression, thereby inhibition of STAT3 has been identified as a potential therapeutic target for the treatment of HNSCC (16,18,62). STAT3 constitutive activation in HNSCC is driven by a number of upstream signal transduction pathways.…”

Section: Discussionmentioning

confidence: 99%

“…There is compelling evidence that STAT3 constitutive activation, mainly associated with aberrant TGF-α/EGFR signaling, is linked to HNSCC development and growth (2,(14)(15)(16)(17)(18). Previous findings suggested the existence of EGFRindependent STAT oncogenic properties in HNSCC, including autocrine/paracrine cytokine (IL-6, IL-10 or IL-22) stimulation or signaling through 7 nicotinic and erythropoietin receptor pathways (17,(19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…The STAT3 signalling pathways regulate the gene expression of proliferation, survival, migration and invasion, as well as angiogenesis (2,20) in human. Furthermore, STAT3 is essential at early stages of embryo development (21) and modulates embryonic stem cell differentiation such as TH17 helper T cells (22).…”

Section: Biology Of Stat3mentioning

confidence: 99%

STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers

Wang

Crowe

Goldstein

et al. 2012

International Journal of Oncology

171

133

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“…Several dysregulated proinflammatory signaling cascades including NF-kB, STAT3, and serine/threonine protein kinase B (AKT) have been linked to the carcinogenesis of HNSCC and play a pivotal role in the growth, proliferation, and survival of the head and neck cancer (6)(7)(8)(9)(10). For example, Sen and colleagues recently reported that STAT3 activation can even contribute to EGF receptor inhibitor resistance in HNSCC and thereby targeting of STAT3 may represent an effective treatment strategy (10).…”

Section: Introductionmentioning

confidence: 99%

Garcinol, a Polyisoprenylated Benzophenone Modulates Multiple Proinflammatory Signaling Cascades Leading to the Suppression of Growth and Survival of Head and Neck Carcinoma

Shanmugam

Chen

et al. 2013

Cancer Prevention Research

167

121

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Constitutive activation of proinflammatory transcription factors such as STAT3 and NF-kB plays a pivotal role in the proliferation and survival of squamous cell carcinoma of the head and neck (HNSCC). Thus, the agents that can modulate deregulated STAT3 and NF-kB activation have a great potential both for the prevention and treatment of HNSCC. In the present report, we investigated the potential effects of garcinol, an active component of Garcinia indica on various inflammatory mediators involved in HNSCC progression using cell lines and xenograft mouse model. We found that garcinol inhibited constitutively activated STAT3 in HNSCC cells in a time-and dose-dependent manner, which correlated with the suppression of the upstream kinases (c-Src, JAK1, and JAK2) in HNSCC cells. Also, we noticed that the generation of reactive oxygen species is involved in STAT3 inhibitory effect of garcinol. Furthermore, garcinol exhibited an inhibitory effect on the constitutive NF-kB activation, mediated through the suppression of TGF-b-activated kinase 1 (TAK1) and inhibitor of IkB kinase (IKK) activation in HNSCC cells. Garcinol also downregulated the expression of various gene products involved in proliferation, survival, and angiogenesis that led to the reduction of cell viability and induction of apoptosis in HNSCC cells. When administered intraperitoneally, garcinol inhibited the growth of human HNSCC xenograft tumors in male athymic nu/nu mice. Overall, our results suggest for the first time that garcinol mediates its antitumor effects in HNSCC cells and mouse model through the suppression of multiple proinflammatory cascades. Cancer Prev Res; 6(8);

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STAT3 as a therapeutic target in head and neck cancer

Cited by 204 publications

References 114 publications

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

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

STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers

Garcinol, a Polyisoprenylated Benzophenone Modulates Multiple Proinflammatory Signaling Cascades Leading to the Suppression of Growth and Survival of Head and Neck Carcinoma

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