Antithetical
            <scp>NFAT</scp>
            c1–Sox2 and p53–miR200 signaling networks govern pancreatic cancer cell plasticity

Singh, Shiv K.; Chen, Nai‐Ming; Heßmann, Elisabeth; Siveke, Jens T.; Lahmann, Marlen; Singh, Garima; Voelker, Nadine; Vogt, Sophia; Espósito, Irene; Schmidt, Ansgar; Brendel, Cornelia; Stiewe, Thorsten; Gaedcke, Jochen; Mernberger, Marco; Crawford, Howard C.; Bamlet, William R.; Zhang, Jin‐San; Li, Xiao‐Kun; Smyrk, Thomas C.; Billadeau, Daniel D.; Hebrok, Matthias; Neeße, Albrecht; Köenig, Alexander; Ellenrieder, Volker

doi:10.15252/embj.201489574

Cited by 91 publications

(94 citation statements)

References 58 publications

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“…A recent study points to an interesting connection between SOX2 and NFATc1. Knockdown of NFATc1, which is often overexpressed in PDAC, leads to a decrease in SOX2 expression, and this appears to be due to a direct effect of NFATc1 on SOX2 transcription [62]. In other studies, stable overexpression of SOX2 in Patu8988t PDAC cells, which do not express detectable levels of endogenous SOX2, has been shown to increase expression of Twist, Snail and Slug, while decreasing the expression of E-Cadherin and ZO-1 [23].…”

Section: Discussionmentioning

confidence: 99%

SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 – a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC.

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Section: Discussionmentioning

confidence: 99%

SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

et al. 2016

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“…NFAT (Nuclear factor of activated T cells) proteins are oncogenic transcription factors, which are induced upon inflammatory conditions and act as crucial promoters of Kras-induced pancreatic cancer progression and cellular plasticity (26). Moreover, nuclear NFAT is highly overexpressed in the majority of invasively growing pancreatic cancers (27–30).…”

Section: Introductionmentioning

confidence: 99%

GSK-3β Governs Inflammation-Induced NFATc2 Signaling Hubs to Promote Pancreatic Cancer Progression

Baumgart

Chen

Zhang

et al. 2016

Molecular Cancer Therapeutics

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We aimed to investigate the mechanistic, functional and therapeutic role of GSK-3β in the regulation and activation of the pro-inflammatory oncogenic transcription factor NFATc2 in pancreatic cancer. Immunohistochemistry, quantitative real-time polymerase chain reaction, immunoblotting, immunofluorescence microscopy and proliferation assays were used to analyze mouse and human tissues and cell lines. Protein-protein interactions and promoter regulation were analyzed by co-immunoprecipitation, DNA pull-down, reporter, and ChIP assays. Preclinical assays were performed using a variety of pancreatic cancer cells lines, xenografts and a genetically engineered mouse model (GEMM). GSK-3β-dependent SP2 phosphorylation mediates NFATc2 protein stability in the nucleus of pancreatic cancer cells stimulating pancreatic cancer growth. In addition to protein stabilization, GSK-3β also maintains NFATc2 activation through a distinct mechanism involving stabilization of NFATc2-STAT3 complexes independent of SP2 phosphorylation. For NFATc2-STAT3 complex formation, GSK-3β-mediated phosphorylation of STAT3 at Y705 is required to stimulate euchromatin formation of NFAT target promoters such as cyclin dependent kinase −6 (CDK-6), which promotes tumor growth. Finally, preclinical experiments suggest that targeting the NFATc2-STAT3-GSK-3β module inhibits proliferation, tumor growth, and interferes with inflammation-induced pancreatic cancer progression in KrasG12D mice. In conclusion, we describe a novel mechanism by which GSK-3β fine-tunes NFATc2 and STAT3 transcriptional networks to integrate upstream signaling events that govern pancreatic cancer progression and growth. Furthermore, the therapeutic potential of GSK-3β is demonstrated for the first time in a relevant Kras and inflammation-induced GEMM for pancreatic cancer.

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“…It has been established that garcinol treatment is associated with an increase in several antioncogenic miR molecules including miR‐200c. Equally important, miR‐200c has been shown to be an essential key molecule in controlling tumorigenesis in several cancer types including pancreatic cancer . Thus, we selected miR‐200c and evaluated its role in PANC‐1 cells.…”

Section: Resultsmentioning

confidence: 99%

Garcinol downregulates Notch1 signaling via modulating miR‐200c and suppresses oncogenic properties of PANC‐1 cancer stem‐like cells

Huang

Lin

Huang

et al. 2017

Biotech and App Biochem

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Pancreatic cancer represents one of the most aggressive types of malignancy due to its high resistance toward most clinically available treatments. The presence of pancreatic cancer stem-like cells (CSCs) has been attributed to the intrinsically high resistance and highly metastatic potential of this disease. Here, we identified and isolated pancreatic CSCs using the side population (SP) method from human pancreatic cancer cell line, PANC-1. We then compared the SP and non-SP PANC-1 cells genetically. PANC-1 SP cells exhibited CSC properties including enhanced self-renewal ability, increased metastatic potential, and resistance toward gemcitabine treatment. These cancer stem-like phenotypes were supported by their enhanced expression of ABCG2, Oct4, and CD44. A traditional plant-derived antioxidant, garcinol, has been implicated for its anticancer properties. Here, we found that garcinol treatment to PANC-1 SP cells significantly suppressed the stem-like properties of PANC-1 SP cells and metastatic potential by downregulating the expression of Mcl-1, EZH2, ABCG2, Gli-1, and Notch1. More importantly, garcinol treatment led to the upregulation of several tumor suppressor microRNAs, and miR-200c increased by garcinol treatment was found to target and downregulate Notch1. Thus, PANC-1 SP cells may serve as a model for studying drug-resistant pancreatic CSCs, and garcinol has the potential as an antagonist against pancreatic CSCs.

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Antithetical NFAT c1–Sox2 and p53–miR200 signaling networks govern pancreatic cancer cell plasticity

Cited by 91 publications

References 58 publications

SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

GSK-3β Governs Inflammation-Induced NFATc2 Signaling Hubs to Promote Pancreatic Cancer Progression

Garcinol downregulates Notch1 signaling via modulating miR‐200c and suppresses oncogenic properties of PANC‐1 cancer stem‐like cells

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