ag-490 and Skin-Neoplasms
ag-490 has been researched along with Skin-Neoplasms* in 4 studies
Other Studies
4 other study(ies) available for ag-490 and Skin-Neoplasms
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Pre-mRNA processing factor 3 enhances the progression of keratinocyte-derived cutaneous squamous cell carcinoma by regulating the JAK2/STAT3 pathway.
The precise role of pre-mRNA processing factors (PRPs) in human tumorigenesis has not been yet explored. The object of the present study was to explore the effects of PRP3 in a common metastatic skin cancer, keratinocyte-derived cutaneous squamous cell carcinoma (cSCCs). RT-qPCR and western blotting were conducted to measure the expression levels of PRP3 in various cSCC cell lines and cSCC tissues. A benign epidermal keratinocyte cell line was transfected with a eukaryotic expression plasmid to overexpress PRP3. In addition, the endogenous expression level of PRP3 in cSCC cells was silenced using a short hairpin RNA method, and the role of PRP3 on cell proliferation and migration was examined by Cell Counting Kit-8, colony formation, wound healing assay and Transwell assays following knockdown in cSCC cells, and overexpression in keratinovcyte cells. Elevated levels of PRP3 mRNA and protein were noted in cSCC cell lines or cSCC tissues compared with actinic keratosis (AK) or benign epidermal keratinocyte cell line, respectively. Upregulation of PRP3 expression was found to be associated with poor clinical outcomes in patients with cSCCs. The upregulation of PRP3 promoted cell viability, metastasis and the activity of the JAK2/STAT3 pathway in epidermal keratinocyte cells. Interestingly, loss of PRP3 had no obvious impact on cell viability and migration in benign epidermal keratinocyte cells. Functionally, the inhibition of the JAK2/STAT3 pathway reversed the increased cell viability and migration of cSCC cells induced by PRP3. Taken together, the present observations indicated that PRP3 served as a tumor active factor in cSCCs by targeting the JAK2/STAT3 pathway. Moreover, it is implied that impeding the PRP3 activity may selectively constrain cancer cell growth and migration with limited effect on normal skin cells. Topics: Carcinoma, Squamous Cell; Cell Line; Cell Movement; Cell Proliferation; Humans; Janus Kinase 2; Keratinocytes; Keratosis, Actinic; Middle Aged; Neoplasm Metastasis; Nuclear Proteins; Prognosis; Ribonucleoprotein, U4-U6 Small Nuclear; RNA Interference; RNA, Small Interfering; Signal Transduction; Skin Neoplasms; STAT3 Transcription Factor; Survival Rate; Tyrphostins; Up-Regulation | 2020 |
Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells.
Interleukin-2 (IL-2) is a growth factor which upon binding to high-affinity receptors (IL-2Ralphabetagamma) triggers mitogenesis in T cells. IL-2Ralpha expression is restricted to T cells which have recently encountered antigen, and in healthy individuals the majority (>95%) of peripheral T cells are IL-2Ralpha negative. An aberrant expression of IL-2Ralpha has recently been described in cutaneous T-cell lymphoma (CTCL). Here, we study the regulation of IL-2Ralpha expression and STATs in a tumor cell line obtained from peripheral blood from a patient with Sezary syndrome (SS), a leukemic variant of CTCL. We show that (1) STAT3 (a transcription factor known to regulate IL-2Ralpha transcription) is constitutively tyrosine-phosphorylated in SS tumor cells, but not in non-malignant T cells; (2) STAT3 binds constitutively to a STAT-binding sequence in the promotor of the IL-2Ralpha gene; (3) the Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel; and (4) tyrphostine AG490 inhibits IL-2 driven mitogenesis and triggers apoptosis in SS tumor cells. In conclusion, we provide the first example of a constitutive STAT3 activation in SS tumor cells. Moreover, our findings suggest that STAT3 activation might play an important role in the constitutive IL-2Ralpha expression, survival, and growth of malignant SS cells. Topics: Antineoplastic Agents; Apoptosis; DNA-Binding Proteins; Humans; Janus Kinase 3; Phosphorylation; Protein-Tyrosine Kinases; Receptors, Interleukin-2; Sezary Syndrome; Skin Neoplasms; STAT3 Transcription Factor; Trans-Activators; Tumor Cells, Cultured; Tyrphostins | 2001 |
Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells.
The Jak/Stat signaling pathway transmits signals from many cytokine and growth factor receptors to target genes in the nucleus. Constitutive activation of Stat3 has recently been observed in many tumor cells and dysregulation of the Stat signaling pathway has been proposed to be implicated in malignant transformation. In a previous study, we found constitutively tyrosine phosphorylated Stat3 in mycosis fungoides tumor cells. Here, we show that the Jak kinase inhibitor, Ag490, inhibits the constitutive binding of Stat3 to an oligonucleotide representing the Stat-binding sequence from the ICAM promotor. The decreased ability of Stat3 to bind DNA precedes dynamic alterations in the expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins (decreased Bcl-2 expression and increased Bax expression) and induction of apoptosis. Thus, our data suggest that the involvement of Stat3 in oncogenic transformation could be mediated through regulation of survival signals. Topics: Animals; Apoptosis; bcl-2-Associated X Protein; DNA-Binding Proteins; Enzyme Inhibitors; Humans; Mycosis Fungoides; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rabbits; Skin Neoplasms; STAT3 Transcription Factor; Trans-Activators; Tumor Cells, Cultured; Tyrphostins | 1999 |
Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: tyrphostin AG490 inhibits Stat3 activation and growth of mycosis fungoides tumor cell lines.
Mycosis fungoides (MF) is a low-grade cutaneous T cell lymphoma of unknown etiology. In this report, the Jak/Stat (Janus kinase/signal transducer and activator of transcription) signaling pathway was investigated in tumor cell lines established from skin biopsy specimens from a patient with MF. Jaks link cytokine receptors to Stats, and abnormal Jak/Stat signaling has been observed in some hemopoietic cancers. In MF tumor cells, a slowly migrating isoform of Stat3, Stat3(sm), was found to be constitutively activated, i.e., (i) Stat3(sm) was constitutively phosphorylated on tyrosine residues, and tyrosine phosphorylation was not enhanced by growth factor stimulation; (ii) band shift assays and immunoprecipitations of DNA/Stat complexes showed constitutive DNA-binding properties of Stat3(sm); and (iii) Stat3(sm) was constitutively associated with Jak3. The abnormal activation of Stat3(sm) was highly specific. Thus, neither the fast migrating isoform of Stat3 (Stat3(fm)) nor other Stats (Stat1, Stat2, and Stat4 through Stat6) were constitutively activated. The Jak kinase inhibitor, tyrphostin AG490, blocked the constitutive activation of Stat3(sm) and inhibited spontaneous as well as interleukin 2-induced growth of MF tumor cells. In conclusion, we have provided evidence for an abnormal Jak/Stat signaling and growth regulation in tumor cells obtained from affected skin of an MF patient. Topics: Cell Division; DNA-Binding Proteins; Enzyme Activation; Enzyme Inhibitors; Humans; Interleukin-2; Mycosis Fungoides; Nitriles; Signal Transduction; Skin Neoplasms; STAT3 Transcription Factor; Trans-Activators; Tumor Cells, Cultured; Tyrphostins | 1997 |