Defective Jak-STAT signal transduction pathway in melanoma cells resistant to growth inhibition by interferon-?

Pansky, Andreas; Hildebrand, Pius; Fasler‐Kan, Elizaveta; Baselgia, Luisa; Ketterer, Sylvia; Beglinger, Christoph; Heim, Markus H.

doi:10.1002/(sici)1097-0215(20000301)85:5<720::aid-ijc20>3.0.co;2-o

Cited by 96 publications

(74 citation statements)

References 15 publications

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“…These results are in agreement with data obtained by using different technologies, suggesting the presence of relatively functional signal transduction in IFN-α insensitive cells (Ralph et al, 1995;Wong et al, 1997). Interestingly, similar results were also obtained by testing some of the cell lines under investigation in the current work by conventional gene and protein expression techniques (Pansky et al, 2000).…”

Section: Discussionsupporting

confidence: 92%

High density oligonucleotide array analysis of interferon-α2a sensitivity and transcriptional response in melanoma cells

et al. 2001

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Summary Interferon alpha (IFN-α) represents an adjuvant therapy of proven effectiveness in increasing disease-free interval and survival in subgroups of melanoma patients. Since high doses of cytokine are required, the treatment is often accompanied by toxic side effects. Furthermore, naturally occurring insensitivity to IFN-α may hamper its therapeutic efficacy. Clinical, molecular or immunological markers enabling the selection of potential responders have not been identified so far. To explore the molecular basis of IFN-α responsiveness, we analysed the expression pattern of about 7000 genes in IFN-α sensitive and resistant cell lines and we compared the transcription profiles of cells cultured in the presence or absence of the cytokine using high-density oligonucleotide arrays. Melanoma cell lines were screened for their sensitivity to proliferation inhibition and HLA class I induction upon IFN-α treatment by standard 3H-thymidine incorporation and flowcytometry. The study of 4 sensitive and 2 resistant cell lines allowed the identification of 4 genes (RCC1, IFI16, hox2 and h19) preferentially transcribed in sensitive cells and 2 (SHB and PKC-ζ) preferentially expressed in resistant cells. IFN-α stimulation resulted in the expression of a panel of 19 known inducible genes in sensitive but not in resistant cells. Moreover a group of 30 novel IFN-α inducible genes was identified. These data may provide a useful basis to develop diagnostic tools to select potential IFN-α responders eligible for treatment, while avoiding unnecessary toxicity to non-responders. Furthermore, by extending the knowledge of the polymorphic effects of IFN-α on gene expression, they offer novel clues to the study of its pleiotropic toxicity.

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Section: Discussionsupporting

confidence: 92%

High density oligonucleotide array analysis of interferon-α2a sensitivity and transcriptional response in melanoma cells

et al. 2001

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“…In a recent study, activated STAT1 was also shown to negatively regulate angiogenesis, tumorigenicity and metastasis of tumour cells (Huang et al, 2002). STAT1 deficiency has also been found in a variety of tumour cell lines and this deficiency is responsible for the lack of INF-g-mediated tumour suppression effects (Wong et al, 1997;Abril et al, 1998;Sun et al, 1998;Pansky et al, 2000). Therefore, it was not unexpected that constitutively activated STAT1 was found in only eight (13.1%) of the 61 NPC specimens.…”

Section: Discussionmentioning

confidence: 98%

Constitutive activation of STAT3 and STAT5 is present in the majority of nasopharyngeal carcinoma and correlates with better prognosis

et al. 2003

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Constitutively activated signal transducers and activators of transcription (STAT) factors, in particular STAT1, STAT3 and STAT5, have been demonstrated in a variety of human tumours and cancer cell lines. However, data on the expression of these STATs in nasopharyngeal carcinoma (NPC) are limited. In this study, the expression patterns of STAT1, STAT3 and STAT5 were immunohistochemically examined on the archival specimens from 61 patients with NPC. Staining results of each STATs were then correlated with the clinical parameters and prognosis of these patients. The results showed that constitutive activation of STAT3 and STAT5 was detected in the majority, 70.5 and 62.3%, respectively, of the 61 tumour specimens. Furthermore, coexpression of activated STAT3 and STAT5 was found in 54.1% of the specimens. In contrast, constitutive activated STAT1 could only be detected in 8 (13.1%) cases. Surprisingly, following radiotherapy, patients with constitutive STAT5 activation, or activation of both STAT3 and STAT5, had better disease-free survival and overall survival than those without activated STAT5. To our knowledge, this is the first report providing the overall expression patterns and prognostic significance of specific STATs in NPC.

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“…It would be relevant to search for correlations between the accumulation of the STAT3 monomeric forms and its possible molecular alterations in early and advanced STAT3 signaling and tumor cell invasion C Rivat et al stages of colorectal tumor progression. In the established melanoma cell line D10, a defect of STAT3 tyrosine phosphorylation was found to be responsible for resistance to the growth inhibitory effects of IFN-a (Pansky et al, 2000). Defects in STAT3 tyrosine phosphorylation may involve increased phosphatase activity or sustained STAT3 serine phosphorylation through MAPK pathway (Chung et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell–cell adhesion complexes

et al. 2004

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STAT3 is frequently overexpressed and constitutively activated by tyrosine phosphorylation during malignant transformation. Despite the clear importance of STAT3 in cell proliferation and survival in diverse human cancers, its possible contribution to tumor cell adhesion, motility and invasion remains hypothetical. We therefore compared the transforming properties of STAT3wt, its constitutively activated dimeric form STAT3C, and the dominant negative mutant STAT3-Y705F in human colorectal HCT8/S11 cancer cells. Both STAT3wt and STAT3C exert a permissive action to the proinvasive activity of the scatter factor HGF in HCT8/S11 cells. In contrast, the monomeric and cytoplasmic mutant Y705F induces a constitutive invasive phenotype through Wnt/Rho-independent and EGFR/PI3-kinase-dependent pathways. Accordingly, Y705F decreases cell-cell homotypic adhesions, and increases cell motility and scattering, as well as lamellipodia-type cellular extensions. STAT3-Y705F-transfected HCT8/S11 cells display an increased tyrosine phosphorylation of the cell-cell adhesion regulator bcatenin and its dissociation from the invasion suppressor E-cadherin at cell-cell contacts. Our data imply that both invasion promoter and repressor genes are controlled by the canonical STAT3 transcription pathways. Disruption of this cascade by Y705F reveals the proinvasive potential of altered forms of STAT3 as a persistent signaling adaptor in cytokine/transforming growth factor receptor scaffolds and oncogenic pathways.

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Defective Jak-STAT signal transduction pathway in melanoma cells resistant to growth inhibition by interferon-?

Cited by 96 publications

References 15 publications

High density oligonucleotide array analysis of interferon-α2a sensitivity and transcriptional response in melanoma cells

High density oligonucleotide array analysis of interferon-α2a sensitivity and transcriptional response in melanoma cells

Constitutive activation of STAT3 and STAT5 is present in the majority of nasopharyngeal carcinoma and correlates with better prognosis

Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell–cell adhesion complexes

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