Kortylewski M, Jove R, Yu H.. Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev 24: 315-327

Immunology Program, USA.
Cancer and metastasis reviews (Impact Factor: 7.23). 07/2005; 24(2):315-27. DOI: 10.1007/s10555-005-1580-1
Source: PubMed


As a point of convergence for numerous oncogenic signaling pathways, STAT3 is constitutively-activated at 50 to 90% frequency in diverse human cancers, including melanoma. A critical role of STAT3 in tumor cell survival, proliferation, angiogenesis, metastasis and immune evasion has been recently demonstrated. STAT3 contributes to tumor cell growth by regulating the expression of genes that are involved in cell survival and proliferation. STAT3 promotes metastasis and angiogenesis by inducing expression of the metastatic gene, MMP-2, and the potent angiogenic gene, VEGF. STAT3 participates in the regulation of tumor immune evasion by inhibiting expression of proinflammatory mediators while promoting expression of immune-suppressing factors, which in turn activates STAT3 signaling in dendritic cells leading to immune tolerance. Thus, targeting STAT3 for therapy assaults cancer on multiple fronts. Many of the studies that defined STAT3's role in oncogenesis were carried out in melanoma cells and tumor models. In this review, we summarize the key role of STAT3 in cancer in general and melanoma in particular. With the emergence of small-molecule drugs that directly inhibit STAT3 or the oncogenic signaling pathways upstream of STAT3 in melanoma, a promising novel approach for melanoma therapy is emerging.

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Available from: Marcin Kortylewski, Jan 19, 2016
    • "STAT3 protein levels are increased in B16 melanoma cells following B-1 contact STAT3 is an important transcription factor that helps regulate malignant progression, tumor cell proliferation, survival, angiogenesis , metastasis and immune evasion (Kortylewski et al. 2005). Table 1 Molecular function enriched in genes that were differentially expressed in B16 melanoma cells after co-culture with B-1 lymphocytes. "
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    ABSTRACT: The analysis of gene expression patterns in cancers has improved the understanding of the mechanisms underlying the process of metastatic progression. However, the acquisition of invasive behavior in melanoma is poorly understood. In melanoma, components of the immune system can contribute to tumor progression, and inflammatory cells can influence almost all aspects of cancer progression, including metastasis. Recent studies have attributed an important role to B-1 cells, a subset of B lymphocytes, in melanoma progression. In vitro interactions between B16 melanoma cells and B-1 lymphocytes lead to increased B16 cell metastatic potential, but the molecular changes induced by B-1 lymphocytes on B16 cells have not yet been elucidated. In this study, we used a microarray approach to assess the gene expression profile of B16 melanoma cells following contact with B-1 lymphocytes (B16B1). The microarray analysis identified upregulation in genes involved with metastatic progression, such as ctss, ccl5, cxcl2 and stat3. RT-qPCR confirmed this increase in mRNA expression in B16B1 samples. As previous studies have indicated that the ERK1/2 MAPK cascade is activated in melanoma cells following contact with B-1 lymphocytes, RT-qPCR was performed with RNA from melanoma cells before and after contacting B-1 cells and untreated or treated with ERK phosphorylation inhibitors. The results showed that the expression of stat3, ctss and cxcl2 increased in B16B1 but decreased following ERK1/2 MAPK inhibition. Ccl5 gene expression increased after contacting B-1 cells and was maintained at the same level following inhibitor treatment. Stat3 was verified and validated at the protein level by Western blot analysis. STAT3 expression was also significantly increased in B16B1, suggesting that this pathway can also contribute to the increased metastatic phenotype observed in our model. These results indicated that B-1 cells induce important global gene expression changes in B16 melanoma cells. We also evaluated the relationship of some of the genes identified as differentially expressed and the ERK1/2 MAPK cascade. This work may have important implications for understanding the role of B-1 lymphocytes and the ERK/MAPK cascade in the metastatic process.
    No preview · Article · May 2013 · Immunobiology
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    • "Activation of proliferation and survival signaling pathways also contribute to chemoresistance. Signal Transducer and Activator of Transcription (STAT3) and NF-κB transcription factors, promote oncogenesis, increasing proliferation, survival, invasion, and metastasis by promoting transcription of pro-proliferative, pro-invasive, and anti-apoptotic genes [11]–[14]. The NF-κB family, which consists of p65 (RelA), RelB, p50/105 (NF-κB1), c-Rel, and p52/p100 (NF-κB2), are constitutively activated in many cancers [14]. "
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    ABSTRACT: Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis.
    Full-text · Article · Jan 2013 · PLoS ONE
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    • "Here, we demonstrate that PAX3 silencing inhibits growth in melanomas with acquired resistance to vemurafenib. The Jak2-Stat3 pathway is emerging as a target of interest for melanoma (Krasilnikov et al., 2003; Kortylewski et al., 2005; Smalley and Herlyn, 2005). In malignant cells, Stat3 functions in regulating cell proliferation, angiogenesis and inhibition of apoptosis (Zushi et al., 1998; Catlett-Falcone et al., 1999; Amin et al., 2004). "
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    ABSTRACT: Vemurafenib (PLX4032), a selective inhibitor of Braf, has been FDA-approved for the treatment of unresectable or metastatic melanoma in patients with Braf(V600E) mutations. Many patients treated with vemurafenib initially display dramatic improvement, with decreases in both risk of death and tumor progression. Acquired resistance, however, rapidly arises in previously sensitive cells. We attempt to overcome this resistance by targeting the Stat3-PAX3 signaling pathway, which is upregulated, due to FGF2 secretion or increased kinase activity, with the Braf(V600E) mutation. We found that activation of Stat3 or overexpression of PAX3 induced resistance to vemurafenib in melanoma cells. Additionally, PAX3 or Stat3 silencing inhibited the growth of melanoma cells with acquired resistance to vemurafenib. Furthermore, treatment with the Stat3 inhibitor, WP1066, resulted in growth inhibition in both vemurafenib-sensitive and -resistant melanoma cells. Significantly, vemurafenib stimulation induced FGF2 secretion from keratinocytes and fibroblasts, which might uncover, at least in part, the mechanisms underlying targeting Stat3-PAX3 signaling to overcome the acquired resistance to vemurafenib. Our results suggest that Stat3-targeted therapy is a new therapeutic strategy to overcome the acquired resistance to vemurafenib in the treatment of melanoma.Journal of Investigative Dermatology accepted article preview online, 23 January 2013; doi:10.1038/jid.2013.32.
    Full-text · Article · Jan 2013 · Journal of Investigative Dermatology
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