Blocking IL-6/GP130 Signaling Inhibits Cell Viability/Proliferation, Glycolysis, and Colony Forming Activity in Human Pancreatic Cancer Cells

Chen, Xiang; Tian, Jilai; Su, Gloria H.; Lin, Jiayuh

doi:10.2174/1568009618666180430123939

Cited by 25 publications

(22 citation statements)

References 65 publications

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“…Subsequently, it suppresses STAT3 phosphorylation and transcription induced by IL6. Various studies have shown Bazedoxifene could inhibit tumor growth by targeting the IL-6/GP130/STAT3 signaling pathway (Wu et al, 2016;Xiao et al, 2017;Chen et al, 2019;Ma et al, 2019). Based on our study, we found Bazedoxifene could attenuate the formation and severity of aneurysms, which may expand the application of Bazedoxifene to the prevention and treatment of abdominal aortic aneurysms in clinics.…”

Section: Discussionsupporting

confidence: 59%

Bazedoxifene Attenuates Abdominal Aortic Aneurysm Formation via Downregulation of Interleukin-6/Glycoprotein 130/Signal Transducer and Activator of Transcription 3 Signaling Pathway in Apolipoprotein E–Knockout Mice

Yan

Shi

et al. 2020

Front. Pharmacol.

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Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by aortic dilatation and predominantly affects an elderly population. Accumulating evidence suggests that Interleukin-6 (IL-6) and the signal transducer and activator of transcription 3 (STAT3) play an important role in formation of AAAs. However, it remains unclear whether Bazedoxifene (BAZ) could suppress the activation of IL-6/GP130/STAT3 in vascular cells and the formation of AAA. Here we explored the effect of BAZ on AngII-stimulated AAA formation. ApoE-/mice infused with AngII for 28 days using osmotic minipumps were treated with placebo or 5mg/kg BAZ. In our results most of the AngII-induced mice developed AAA with exacerbated inflammation, degradation of elastin fibers, STAT3 phosphorylation, and increased expression of matrix metalloproteinases (MMPs). These effects were markedly attenuated by BAZ. Furthermore, BAZ suppressed the stimuliinduced (IL-6 or AngII) expression of P-STAT3, MMP2 and MMP9 in vascular smooth muscle cells (VSMCs). BAZ inhibited wound healing, colony formation and suppressed STAT3 nuclear translocation in vitro. In conclusion, these results indicated that BAZ downregulated IL-6/GP130/STAT3 signaling and interfered with AAA formation induced by AngII in ApoE-/mice, which indicates a novel potential strategy for the prevention and therapy of AAA.

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Section: Discussionsupporting

confidence: 59%

Bazedoxifene Attenuates Abdominal Aortic Aneurysm Formation via Downregulation of Interleukin-6/Glycoprotein 130/Signal Transducer and Activator of Transcription 3 Signaling Pathway in Apolipoprotein E–Knockout Mice

Yan

Shi

et al. 2020

Front. Pharmacol.

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“…IL-6 seems to play an important role in pancreatic cancer, with several studies indicating that high levels of IL-6 expression are associated with a significantly lower survival and a poor response to therapy ( 26 – 28 ). Therefore, the IL-6 signaling pathway may serve as a promising therapeutic target for pancreatic cancer ( 29 , 30 ). Our results have revealed that nsPEFs substantially inhibit the secretion of IL-6, which can limit T lymphocyte-driven antitumor immunity by reducing immune suppressive cells, such as myeloid-derived suppressor cells and regulatory T cells (Treg).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Effect and Immune Response of Nanosecond Pulsed Electric Fields in Pancreatic Cancer

et al. 2021

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Nanosecond pulsed electric fields (nsPEFs) have emerged as a novel and effective strategy for the non-surgical and minimally invasive removal of tumors. However, the effects of nsPEFs treatment on the tumor immune microenvironment remain unknown. In this study, the changes in the morphology and function of pancreatic cancer cells after nsPEFs were assessed and the modifications in the immune profile in pancreatic cancer models were investigated. To this end, electrodes were inserted with different parameters applied to ablate the targeted tumor tissues. Tumor development was found to be inhibited, with decreased volumes post-nsPEFs treatment compared with control tumors (P < 0.05). Hematoxylin and eosin staining showed morphological changes in pancreatic cancer cells, Ki-67 staining confirmed the effects of nsPEFs on tumor growth, and caspase-3 staining indicated that nsPEFs caused apoptosis in the early stages after treatment. Three days after nsPEFs, positron emission tomography demonstrated little residual metabolic activity compared with the control group. Gene expression profiling identified significant changes in immune-related pathways. After treatment with nsPEFs, CD8+ T lymphocytes increased. We showed that nsPEFs led to a significant decrease in immune suppressive cells, including myeloid derived suppressor cells, T regulatory cells, and tumor-associated macrophages. In addition, the levels of TNF-α and IL-1β increased (P < 0.05), while the level of IL-6 was decreased (P < 0.05). NsPEFs alleviated the immunosuppressive components in pancreatic cancer stroma, including hyaluronic acid and fibroblast activation protein-α. Our data demonstrate that tumor growth can be effectively inhibited by nsPEFs in vivo. NsPEFs significantly altered the infiltration of immune cells and triggered immune response.

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“…As summarized in Table 3 , 25 of the included studies were preclinical trials testing 20 substances targeting the GP130/JAK/STAT3-pathway. Twenty-four studies performed in vitro experiments using human pancreatic cancer cells [ 17 , 27 – 32 , 34 – 36 , 38 – 41 , 43 – 47 , 49 , 50 , 60 , 61 ]. In vivo experiments were performed in 17 studies using mouse xenograft tumor models (n = 14) [ 28 , 31 , 34 , 35 , 38 , 40 – 42 , 44 , 45 , 48 – 50 , 60 ], chicken chorio-allantoic membrane xenograft tumor models (n = 1) [ 32 ], or KPC mice (n = 2) [ 33 , 45 ].…”

Section: Resultsmentioning

confidence: 99%

Therapeutic targeting of STAT3 pathways in pancreatic adenocarcinoma: A systematic review of clinical and preclinical literature

Peisl¹,

Mellenthin²,

Vignot³

et al. 2021

PLoS ONE

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Background/Objectives Pancreatic ductal adenocarcinoma is a highly lethal disease with increasing incidence. Due to high resistance, chemo/radiotherapy has limited success in pancreatic cancer and only marginally prolongs patient survival. Therefore, novel biomarkers and therapeutic targets are needed. In the present review, we performed a comprehensive summary of therapeutic approaches targeting the GP130/JAK/STAT3 pathway. Methods We systematically reviewed the PubMed and Embase databases for preclinical and clinical studies, from inception to October 4, 2020, on drugs targeting the GP130/JAK/STAT3 pathway. Bias assessments and qualitative analyses were performed. Results Twenty-five preclinical and nine clinical trials were included in the review. All preclinical studies reported a favorable outcome in terms of pancreatic ductal adenocarcinoma progression. Futhermore, drugs targeting the GP130/JAK/STAT3 pathway were shown to be efficient chemosensitizers. However, high publication bias was assumed. In the clinical setting, bazedoxifene and itacitinib improved patient outcomes. Conclusion Preclinical studies strongly suggest significant efficacy of drugs targeting GP130/JAK/STAT3 in the treatment of pancreatic ductal adenocarcinoma and that these molecules are effective chemosensitizers. Though only a few trials have shown the efficacy in a clinical setting, the STAT3 pathway remains a promising drug target for future treatment of pancreatic ductal adenocarcinoma and may help overcome chemotherapy resistance.

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Blocking IL-6/GP130 Signaling Inhibits Cell Viability/Proliferation, Glycolysis, and Colony Forming Activity in Human Pancreatic Cancer Cells

Abstract: Our findings demonstrated that IL-6 stimulates pancreatic cancer cell proliferation, survival and glycolysis, and supported persistent IL-6 signaling is a viable therapeutic target for pancreatic cancer using IL-6/GP130 inhibitors.

Cited by 25 publications

References 65 publications

Bazedoxifene Attenuates Abdominal Aortic Aneurysm Formation via Downregulation of Interleukin-6/Glycoprotein 130/Signal Transducer and Activator of Transcription 3 Signaling Pathway in Apolipoprotein E–Knockout Mice

Bazedoxifene Attenuates Abdominal Aortic Aneurysm Formation via Downregulation of Interleukin-6/Glycoprotein 130/Signal Transducer and Activator of Transcription 3 Signaling Pathway in Apolipoprotein E–Knockout Mice

Antitumor Effect and Immune Response of Nanosecond Pulsed Electric Fields in Pancreatic Cancer

Therapeutic targeting of STAT3 pathways in pancreatic adenocarcinoma: A systematic review of clinical and preclinical literature

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