Stat3/Socs3 Activation by IL-6 Transsignaling Promotes Progression of Pancreatic Intraepithelial Neoplasia and Development of Pancreatic Cancer

Lesina, Marina; Kurkowski, Magdalena U.; Ludes, Katharina; Rose-John, Stefan; Treiber, Matthias; Klöppel, Günter; Yoshimura, Akihiko; Reindl, Wolfgang; Sipos, Bence; Akira, Shizuo; Schmid, Roland M.; Algül, Hana

doi:10.1016/j.ccr.2011.03.009

Cited by 726 publications

(650 citation statements)

References 44 publications

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“…In contrast to this, several publications could demonstrate that SOCS3 is frequently inactivated by promoter hypermethylation in different types of cancer, including prostate cancer (21)(22)(23). In addition, homozygous deletion of SOCS3 in a murine pancreatic intraepithelial neoplasia model led to accelerated cancer progression and reduced survival (24). So far, the role of SOCS3 has not been studied in androgen receptor-positive prostate cancer cell lines due to the low basal expression of SOCS3.…”

Section: Introductionmentioning

confidence: 91%

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

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Erb

Luef

et al. 2016

Molecular Cancer Research

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The proinflammatory cytokine IL6 is associated with bad prognosis in prostate cancer and implicated in progression to castration resistance. Suppressor of cytokine signaling 3 (SOCS3) is an IL6-induced negative feedback regulator of the IL6/Janus kinase (JAK)/STAT3 pathway. This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor-positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor-mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced androgen receptor activity after 3 weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly upregulated by the long-term treatment, and modulation of SOCS3 expression was sufficient to counteract this effect. These findings prove that SOCS3 plays an important role during anti-androgen treatment in an inflammatory environment.Implications: SOCS3 is frequently inactivated by promoter hypermethylation in prostate cancer, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines.

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Section: Introductionmentioning

confidence: 91%

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Handle

Erb

Luef

et al. 2016

Molecular Cancer Research

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“…One hypothesis therefore is that PI3K/BMX/mTOR inhibition sensitizes to ABT-737 via repression of STAT3. STAT3 is a key regulator of BCL-x L expression, a key target of ABT-737 (49). However, no treatment effects on BCL-x L expression were noted by 24 hours (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic.

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“…137 Persistent STAT3 activation has been linked not only to inflammation-induced tumorigenesis but also to the formation of premetastatic niches conditioning the sites of future distant metastases. [138][139][140][141] An amplification loop identified in tumors links the sphingosine 1-phosphate (S1P) signaling through the S1P receptor 1 (S1PR1) and the activation of STAT3, which in turn feeds back to upregulate S1PR1. 133 This pathway results in the upregulation of S1PR1 in the tumor microenvironment leading to continuous STAT3 activation in cancer cells inducing the expression of factors that trigger the same pathway in myeloid cells.…”

Section: Molecular Pathways Of Metastasis-promoting Inflammationmentioning

confidence: 99%

Inflammation and skeletal metastasis

Roca

McCauley

2015

BoneKEy Reports

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On the road to metastasis a cancer cell has to overcome two major obstacles: the physical escape from the primary tumor to a distant tissue and the adaptation to the new microenvironment via colonization and the formation of a secondary tumor. Accumulated scientific findings support the hypothesis that inflammation is a critical component of the tumor microenvironment and develops as a result of tumor-induced recruitment of inflammatory cells and their reciprocal interaction with other cells from the tumor network. These interactions modulate immune responses to suppress antitumor immunity and activate feedback amplification signaling loops that link nearly all the cells in the cancer inflammatory milieu. The coordinated regulation of cytokines/chemokines, receptors and other inflammatory mediators enables the different steps of the metastatic cascade. As a target organ for colonization, the bone is rich in inflammatory mediators that are critical for successful cancer growth. In this review, we focus on the inflammatory cells, molecules and mechanisms that facilitate the expansion of cancer cells from the primary tumor to their new 'home' in the skeleton.

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Stat3/Socs3 Activation by IL-6 Transsignaling Promotes Progression of Pancreatic Intraepithelial Neoplasia and Development of Pancreatic Cancer

Cited by 726 publications

References 44 publications

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Inflammation and skeletal metastasis

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