Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells

Song, Lanxi; Turkson, James; Karras, James G.; Jove, Richard; Haura, Eric B.

doi:10.1038/sj.onc.1206479

Cited by 335 publications

(316 citation statements)

References 74 publications

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“…Recent studies have also linked Stat3 to metastatic progression in several different cancers, including prostate, lung, ovary, and gastrointestinal tract (16,18,(20)(21)(22). The influence of Stat3 on the metastatic potential of these cancers occurs through a variety of molecular mechanisms (35,(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

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A novel target for treatment of chordoma: signal transducers and activators of transcription 3

Yang

Schwab

Schoenfeld

et al. 2009

Molecular Cancer Therapeutics

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A major obstacle in the effective treatment of chordoma is that there are no identifiable biomarkers capable of predicting prognosis. Recent research has indicated that signal transducers and activators of transcription (Stat3) may be an important prognostic marker in some cancers, but its role in chordoma tumors has not been elucidated. In this study, the expression of Stat3 was evaluated in chordoma tissue microarray that contains 70 chordoma samples. Cells in the tissue microarray showed nuclear staining for phosphorylated Stat3 in all instances. The level of phosphorylated Stat3 expression correlated with the survival and severity of the disease. Three chordoma cell lines were exposed to SD-1029, a novel inhibitor of Stat3 activation. MTT assay showed that the growth of all chordoma cell lines was inhibited by SD-1029. The expression of Stat3 signaling cascade was inhibited in all chordoma cell lines after treatment with SD-1029. The cytotoxicity of the combination of SD-1029 and chemotherapeutic drugs is significantly better than either agent alone. Phosphorylation of Stat3 in chordoma cells in vitro and cellular proliferation in three-dimensional culture were inhibited by SD-1029. In conclusion, the Stat3 pathway is constitutively activated in chordomas and the level of expression may serve as a predictor for prognosis. Blockade of the Stat3 pathway represents a potential strategy for future treatment.

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Section: Discussionmentioning

confidence: 99%

“…Constitutive activation of Stat3 has been documented in ovarian, breast, colon, prostate, and several other types of cancer (18)(19)(20)(21)(22). Reports indicate that activation of the Stat3 pathway correlates with clinical outcome in several of these cancers, and inhibition of Stat3 activity may exert an anticancer effect (16,23,24).…”

Section: Introductionmentioning

confidence: 99%

A novel target for treatment of chordoma: signal transducers and activators of transcription 3

Yang

Schwab

Schoenfeld

et al. 2009

Molecular Cancer Therapeutics

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“…The cellular functions that STATs modulate to promote oncogenesis have been well-studied, principally through interrupting STAT signaling and observing the phenotypic consequences. For instance, expression of dominant-negative STAT3 induces apoptosis in a number of tumor cells, including multiple myeloma, breast cancer, mycosis fungoides, lung cancer, prostate cancer and melanoma, [20][21][22][23][24][25] suggesting that many malignant cells may be dependent upon STAT3 for survival. While many normal cells can tolerate loss of STAT3, T-cells in mice with a conditional knock-out of STAT3 have impaired survival in response to IL-6.…”

Section: Stat Signaling and Cancermentioning

confidence: 99%

Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis

Alvarez

Frank²

2004

Cancer Biology & Therapy

104

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“…Similarly, JAK/Stat3 pathway was also found to be involved in I-BOP induced COX-2 expression since the activation of Stat3 and the COX-2 expression were blocked by JAK inhibitor. Previous evidences showed that EGF activated Stat3 through Src, EGFR and JAK in A549 cells [52]. Therefore, I-BOP may activate Stat3 through Src, EGFR and JAK pathway since I-BOP may transactivate EGFR.…”

Section: Discussionmentioning

confidence: 89%

Activation of thromboxane receptor α induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells

Wei

Yan

et al. 2007

Biochemical Pharmacology

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Human lung adenocarcinoma A549 cells stably transfected with TPα (A549-TPα) were used to study agonist I-BOP-induced expression of cyclooxygenase-2 (COX-2) and the related mechanisms of induced expression. I-BOP, a TP agonist, induced a time and dose dependent expression of COX-2 in A549-TPα cells as revealed by Western blot and by the synthesis of PGE 2 and TXB 2 which was totally inhibited by COX-2 inhibitors. The signaling pathways of I-BOP-induced COX-2 expression were elucidated by using various inhibitors of the signaling molecules. The effects of these inhibitors were assessed at three different levels of COX-2 expression: protein, enzyme activity and promoter activity. Within MAPK family, both ERK and p38 MAPK but not JNK/SAPK pathways were involved in the induction. Other pathways such as JAK/Stat3 pathway and β-catenin/TCF/LEF pathway also participated in the induction. The activation of key signaling molecules, ERK, p38 MAPK, CREB and NF-κB, involved in the COX-2 transcription was further studied at the phosphorylation step. Activation of ERK and p38 MAPK appeared to be mediated primarily by transactivation of EGFR, whereas activation of CREB and NF-κB was mediated by PKA, PKC and ERK. The role of CREB and NF-κB in I-BOP-induced COX-2 expression was further explored at the COX-2 promoter level. Studies on promoter fragments of different length and mutation of responsive motifs indicated that CRE and NF-κB sites are critical for the COX-2 induction. Distal NF-κB site is essential for the basal induction of the COX-2 transcription, whereas CRE and proximal NF-κB sites are important for the induced transcription. These results indicate that I-BOP induced COX-2 expression through multiple signaling pathways leading to the activation of CREB and NF-κB transcriptional factors and subsequent COX-2 transcription.

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Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells

Cited by 335 publications

References 74 publications

A novel target for treatment of chordoma: signal transducers and activators of transcription 3

A novel target for treatment of chordoma: signal transducers and activators of transcription 3

Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis

Activation of thromboxane receptor α induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells

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