STAT signaling in head and neck cancer

Song, John I.; Grandis, Jennifer R.

doi:10.1038/sj.onc.1203483

Cited by 335 publications

(303 citation statements)

References 57 publications

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“…STAT3 signaling is required for oncogenic transformation by v-Src [108,[190][191][192]. Blocking of STAT3 DNA binding with antisense oligonucleotides or a dominant-negative STAT3 protein, further established the critical role of STAT3 in oncogenesis [128,193,194]. In all cases, inhibition of persistent STAT3 signaling suppressed the transformed phenotype and tumor progression.…”

Section: Role Of Stat3 In Oncogenic Transformationmentioning

confidence: 98%

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

Subramaniam

Shanmugam

Perumal

et al. 2013

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

203

229

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a b s t r a c t a r t i c l e i n f oHepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but patients suffer from various kinds of adverse effects, including hypertension. The signal-transducer-and-activator-of-transcription 3 (STAT3) protein, one of the members of STATs transcription factor family, has been implicated in signal transduction by different cytokines, growth factors and oncogenes. In normal cells, STAT3 activation is tightly controlled to prevent dysregulated gene transcription, whereas constitutively activated STAT3 plays an important role in tumorigenesis through the upregulation of genes involved in anti-apoptosis, proliferation and angiogenesis. Thus, pharmacologically safe and effective agents that can block STAT3 activation have the potential both for the prevention and treatment of HCC. In the present review, we discuss the possible role of STAT3 signaling cascade and its interacting partners in the initiation of HCC and also analyze the role of various STAT3 regulated genes in HCC progression, inflammation, survival, invasion and angiogenesis.

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Section: Role Of Stat3 In Oncogenic Transformationmentioning

confidence: 98%

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

Subramaniam

Shanmugam

Perumal

et al. 2013

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

203

229

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“…Moreover, factors released from cancer cells may activate STAT3 in an autocrine manner and maintain tumor STAT3 activity and oncogenic potential (19,21,36,37). These findings led us to assume that whether TRM-7 cells maintain STAT3 activation by an autocrine loop, and they will likely be more clinically aggressive.…”

Section: Rantes-mediated Stat3 Activationmentioning

confidence: 99%

“…18). High levels of constitutive STAT3 activation are thought to arise from autocrine stimulation (18)(19)(20)(21). Thus, interruption of constitutive STAT3 signaling in tumor cells will likely inhibit expression of several important classes of oncogenic proteins (22).…”

Section: Introductionmentioning

confidence: 99%

STAT3-RANTES Autocrine Signaling Is Essential for Tamoxifen Resistance in Human Breast Cancer Cells

Lee

et al. 2013

Molecular Cancer Research

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The acquisition of tamoxifen resistance is a major therapeutic problem in breast cancer. We developed a tamoxifen-resistant MCF-7 (TRM-7) cell line to elucidate the molecular mechanisms and factors associated with acquisition of such resistance. We showed that phosphorylation of STAT3 at tyrosine 705 (Y705) and RANTES expression are increased in response to tamoxifen in human breast cancer cells. On the basis of these results, we hypothesize that upregulated STAT3 phosphorylation and RANTES may be correlated with the development of drug resistance. Here, we showed that STAT3 and RANTES contribute to the maintenance of drug resistance. STAT3 phosphorylation is constitutively retained via a RANTES autocrine loop, which in turn upregulates antiapoptotic signals in TRM-7 cells. STAT3-RANTES autocrine signaling affected expression of anti-apoptotic BCL-2 family genes and prevented TRM-7 cells from undergoing programmed cell death by inhibiting PARP and caspase-9 cleavage. Subsequently, blockade of STAT3 and RANTES in TRM-7 cells resulted in reduction of antiapoptotic signals, which was rescued by exogenous RANTES treatment; drug resistance was also restored. Taken together, our results suggested that STAT3-RANTES autocrine signaling is essential for maintenance of drug resistance and inhibition of programmed cell death. These mechanisms of STAT3-RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors. Mol Cancer Res; 11(1); 31-42. Ó2012 AACR. IntroductionBreast cancer is the second most common cancer worldwide after lung cancer, the fifth most common cause of cancer death, and the leading cause of cancer death in women. The global burden of breast cancer exceeds that of all other cancers, and its incidence is increasing (1). In women younger than 50 years with breast cancer, chemotherapy increases the 15-year survival rate by 10%,

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“…Constitutive activation of STAT3 is frequently encountered in HNSCC cells and STAT3 inhibition can be considered as an important therapeutic option for the patients (29). To determine the ability of garcinol to modulate STAT3 activation, CAL27 cells were treated with different concentrations of garcinol for various time points and Western blot analysis using antibodies that recognize STAT3 phosphorylation at tyrosine 705 was conducted.…”

Section: Garcinol Inhibits Constitutively Active Stat3 In Hnscc Cellsmentioning

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

173

123

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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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STAT signaling in head and neck cancer

Cited by 335 publications

References 57 publications

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

STAT3-RANTES Autocrine Signaling Is Essential for Tamoxifen Resistance in Human Breast Cancer Cells

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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