Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling

Flashner-Abramson, Efrat; Klein, Shoshana; Mullin, Gerald; Shoshan, Einav; Song, Renduo; Shir, Alexei; Langut, Yael; Bar‐Eli, Menashe; Reuveni, Hadas; Levitzki, Alexander

doi:10.1038/onc.2015.229

Cited by 34 publications

(37 citation statements)

References 26 publications

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“…Our study shows that GV inhibits activation of STAT3 by EGFR in a Src-independent and JAK-dependent manner. This is supported by studies showing that STAT3 activation in melanoma cells relies on JAK or protein-tyrosine phosphatase rather than on Src (Flashner-Abramson et al, 2016;Kreis et al, 2007;). STAT3 has been reported to enhance invasion and metastasis (Fofaria and Srivastava, 2014) and to mediate the acquisition of a stemness phenotype in melanoma cells (Ohanna et al, 2013).…”

Section: Discussionmentioning

confidence: 79%

Down-Regulation of SOX2 Underlies the Inhibitory Effects of the Triphenylmethane Gentian Violet on Melanoma Cell Self-Renewal and Survival

Pietrobono

Morandi

Gagliardi

et al. 2016

Journal of Investigative Dermatology

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Human melanomas contain a population of tumor-initiating cells that are able to maintain the growth of the tumor. We previously showed that the embryonic transcription factor SOX2 is essential for self-renewal and tumorigenicity of human melanoma-initiating cells. However, targeting a transcription factor is still challenging. Gentian violet (GV) is a cationic triphenylmethane dye with potent antifungal and antibacterial activity. Recently, a combination therapy of imiquimod and GV has shown an inhibitory effect against melanoma metastases. Whether and how GV affects melanoma cells remains unknown. Here we show that GV represses melanoma stem cell self-renewal through inhibition of SOX2. Mechanistically, GV hinders EGFR activation and inhibits the signal transducer and activator of transcription-3 [(STAT3)/SOX2] axis. Importantly, we show that GV treatment decreases STAT3 phosphorylation at residue tyrosine 705, thus preventing the translocation of STAT3 into the nucleus and its binding to SOX2 promoter. In addition, GV affects melanoma cell growth by promoting mitochondrial apoptosis and G2 cell cycle arrest. This study shows that in melanoma, GV affects both the stem cell and the tumor bulk compartments, suggesting the potential use of GV in treating human melanoma alone or in combination with targeted therapy and/or immunotherapy.

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Section: Discussionmentioning

confidence: 79%

Down-Regulation of SOX2 Underlies the Inhibitory Effects of the Triphenylmethane Gentian Violet on Melanoma Cell Self-Renewal and Survival

Pietrobono

Morandi

Gagliardi

et al. 2016

Journal of Investigative Dermatology

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“…The impaired STAT3 signaling observed in p38α‐Δ MC and IGF‐1‐Δ MC mice might be an indirect effect due to the reduced amount of STAT3‐activating cytokines secreted by infiltrating immune cells, given the role of IGF‐1 as a chemokine that increases immune cell recruitment to the colon. However, several reports have proposed that STAT3 phosphorylation can be induced by IGF‐1 in various cell types including colonocytes (Zong et al , ; Zhang et al , ; Flashner‐Abramson et al , ; Sanchez‐Lopez et al , ; Yao et al , ; Xu et al , ). Consistent with the above, our results demonstrate that myeloid cell‐specific downregulation of IGF‐1 suffices to decrease colon tumorigenesis induced by AOM/DSS treatment.…”

Section: Discussionmentioning

confidence: 99%

Myeloid p38α signaling promotes intestinal IGF ‐1 production and inflammation‐associated tumorigenesis

et al. 2018

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The protein kinase p38α plays a key role in cell homeostasis, and p38α signaling in intestinal epithelial cells protects against colitis‐induced tumorigenesis. However, little is known on the contribution of p38α signaling in intestinal stromal cells. Here, we show that myeloid cell‐specific downregulation of p38α protects mice against inflammation‐associated colon tumorigenesis. The reduced tumorigenesis correlates with impaired detection in the colon of crucial chemokines for immune cell recruitment. We identify insulin‐like growth factor‐1 (IGF‐1) as a novel mediator of the p38α pathway in macrophages. Moreover, using genetic and pharmacological approaches, we confirm the implication of IGF‐1 produced by myeloid cells in colon inflammation and tumorigenesis. We also show a correlation between IGF‐1 pathway activation and the infiltration of myeloid cells with active p38α in colon samples from patients with ulcerative colitis or colon cancer. Altogether, our results uncover an important role for myeloid IGF‐1 downstream of p38α in colitis‐associated tumorigenesis and suggest the interest in evaluating IGF‐1 therapies for inflammation‐associated intestinal diseases, taking into consideration IGF‐1 signaling and immune cell infiltration in patient biopsies.

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“…pathway is also relevant to the development of melanoma [31][32][33][34]. Therefore, SIRT6 may regulate autophagy via the IGF-AKT pathway in melanoma.…”

Section: Sirt6 Regulated Autophagy Through the Igf-akt Pathway In Melmentioning

confidence: 99%

Aberrant SIRT6 expression contributes to melanoma growth: Role of the autophagy paradox and IGF-AKT signaling

Wang

Guo

et al. 2017

Autophagy

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Melanoma is among the most life-threatening cancers. The pathogenesis of melanoma has not been fully elucidated. Recently, dysregulated macroautophagy/autophagy has been found to play a critical but inconsistent role in modulating melanoma growth at different stages, with the regulatory mechanism unclear. The histone deacetylase SIRT6 (sirtuin 6) is a known autophagy regulator, and its involvement in cancer development has been reported. Therefore, we sought to determine the role of SIRT6 in melanoma growth and detect its possible link with autophagy in the current study. We initially observed that the expression of SIRT6 decreased in primary melanoma but increased in metastatic melanoma compared with melanocytic nevus. Notably, the expression of SIRT6 was significantly correlated with the expression of autophagy biomarkers including MAP1LC3/LC3 and SQSTM1/p62. Furthermore, SIRT6 suppressed the growth of primary melanoma but promoted metastatic melanoma development in an autophagy-dependent way in vitro. Moreover, SIRT6 exerted its regulation on melanoma growth via the IGF-AKT signaling pathway, and the intervention of AKT could partly reverse the effects of SIRT6 on melanoma growth by regulating autophagy. At last, we determined the effects of SIRT6 on melanoma development in vivo. Taken together, our findings demonstrate that the bimodal expression of SIRT6 at different melanoma stages plays a critical role in regulating melanoma growth through an autophagy-dependent manner, which indicates the potential of SIRT6 to be a biomarker and a therapeutic target in melanoma.

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Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling

Cited by 34 publications

References 26 publications

Down-Regulation of SOX2 Underlies the Inhibitory Effects of the Triphenylmethane Gentian Violet on Melanoma Cell Self-Renewal and Survival

Down-Regulation of SOX2 Underlies the Inhibitory Effects of the Triphenylmethane Gentian Violet on Melanoma Cell Self-Renewal and Survival

Myeloid p38α signaling promotes intestinal IGF ‐1 production and inflammation‐associated tumorigenesis

Aberrant SIRT6 expression contributes to melanoma growth: Role of the autophagy paradox and IGF-AKT signaling

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