<i>PDX‐1</i>

Liu, Shi He; Patel, Sanjeet G.; Gingras, Marie Claude; Nemunaitis, John; Zhou, Guisheng; Chen, Changyi; Li, Min; Fisher, William E.; Gibbs, Richard A.; Brunicardi, F. Charles

doi:10.1002/cncr.25629

Cited by 39 publications

(22 citation statements)

References 57 publications

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“…PDX-1 has been implicated in pancreatic tumorigenesis [26-28, 30-32] and shown great promise as a target for the treatment of PDAC [33, 34]. In order to determine whether treatment with metformin decreases PDX-1 transcriptional activity, we used a synthetic human insulin promoter (SHIP)-driven Luciferase-RFP fusion reporter subject to the regulation by PDX-1 (designated as a SHIP-Luc2RFP).…”

Section: Resultsmentioning

confidence: 99%

“…1A). Considering the role of PDX-1 in enhancing PDAC cell growth [32], these results imply that inhibition of PDX-1 expression and function could contribute to the mechanism by which metformin inhibits PDAC cell growth.…”

Section: Resultsmentioning

confidence: 99%

“…We have first demonstrated the oncogenic function of PDX-1 in HEK293 cells by showing its stimulatory effect on cell proliferation, invasion and colony formation [32]. In an effort to investigate the oncogenic mechanism of PDX-1, we performed an antibody- based array screen in our previously generated GFP- PDX-1 stable HEK293 cells [32] to identify PDX-1- interacting proteins. Whole cell lysates from the GFP- PDX-1 stable HEK293 cells were incubated with a membrane filter spotted with antibodies against 400 different signal transduction proteins.…”

Section: Resultsmentioning

confidence: 99%

“…PDX-1 overexpression in PDAC cells induces proliferation accompanied by up-regulation of cyclin D, cyclin E and Cdk2 and down-regulation of p21, p27 and p53, while knockdown of PDX-1 by PDX-1 shRNA reverse the effect of PDX-1 on these cell cycle-related proteins [32]. This means that the mechanism by which PDX-1 exerts its oncogenic functions is mediated by the regulation of a specific set of genes involved in cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…However, several lines of evidence support the notion that PDX-1 is closely associated with pancreatic tumorigenesis. Specifically, 1) PDX-1 expression is markedly elevated in Pancreatic ductal adenocarcinoma (PDAC) [26-28]; 2) elevated PDX-1 expression levels are significantly correlated with metastasis and histological grade in patients with PDAC [26, 27] and PDX-1 expression in PDAC is an independent survival factor [26, 29]; 3) persistent expression of PDX-1 induces metaplasia [30]; 4) PDX- 1 is required for K-Ras G12D to induce the development of pancreatic intraepithelial neoplasia (PanIN), metaplasia and PDAC [31]; and 5) PDX-1 enhances cell proliferation, colony formation, invasion and tumor growth of malignant tumor cells [32]. Silencing PDX-1 efficiently inhibits PDAC cell proliferation in vitro and tumor growth in vivo [33, 34], thus, PDX-1 is a potential therapeutic target in PDAC treatment.…”

Section: Introductionmentioning

confidence: 99%

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Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.

Zhou¹,

Yu²,

Wang³

et al. 2016

CMM

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most potent and perilous diseases known, with a median survival rate of 3-5 months due to the combination of only advanced stage diagnosis and ineffective therapeutic options. Metformin (1,1-Dimethylbiguanide hydrochloride), the leading drug used for type 2 diabetes mellitus, emerges as a potential therapy for PDAC and other human cancers. Metformin exerts its anticancer action via a variety of adenosine monophosphate (AMP)-activated protein kinase (AMPK)- dependent and/or AMPK-independent mechanisms. We present data here showing that metformin down- regulated pancreatic transcription factor pancreatic duodenal homeobox-1 (PDX-1), suggesting a potential novel mechanism by which metformin exerts its anticancer action. Metformin inhibited PDX-1 expression at both protein and mRNA levels and PDX-1 transactivity as well in PDAC cells. Extracellular signal-regulated kinase (ERK) was identified as a PDX-1-interacting protein by antibody array screening in GFP-PDX-1 stable HEK293 cells. Co-transfection of ERK1 with PDX-1 resulted in an enhanced PDX-1 expression in HEK293 cells in a dose-dependent manner. Immunoprecipitation/Western blotting analysis confirmed the ERK-PDX-1 interaction in PANC-1 cells stimulated by epidermal growth factor (EGF). EGF induced an enhanced PDX-1 expression in PANC-1 cells and this stimulation was inhibited by MEK inhibitor PD0325901. Metformin inhibited EGF-stimulated PDX-1 expression with an accompanied inhibition of ERK kinase activation in PANC- 1 cells. Taken together, our studies show that PDX-1 is a potential novel target for metformin in PDAC cells and that metformin may exert its anticancer action in PDAC by down-regulating PDX-1 via a mechanism involving inhibition of ERK signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.

Zhou¹,

Yu²,

Wang³

et al. 2016

CMM

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The Hypofunctional Effect of P335L Single Nucleotide Polymorphism on SSTR5 Function

et al. 2011

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Introduction Somatostatin receptor subtype 5 (SSTR5) mediates the inhibitory effect of somatostatin on insulin expression/secretion and cell proliferation. A number of single nucleotide polymorphisms (SNPs) of SSTR5 have been identified, including P335L, a non-synonymous SNP located in the protein C-terminal region and encrypted by the codons CCG (proline) or CTG (leucine). In the present study, we sought to determine if the P335L SNP affected the cellular function of SSTR5 in human pancreatic cancer as has been reported previously for neuropsychiatric diseases and pituitary adenomas. Methods The P335L germline genotype of 246 patients with pancreatic cancer (213 Caucasians, 16 Hispanics and 17 African Americans), and 17 human pancreatic cell lines was determined with the TaqMan SNP Genotyping assay. Human SSTR5 leucine variant (L335) was generated by performing site-directed mutagenesis using SSTR5 proline variant (P335) as a template. Transient transfections were performed in HEK293, Mia PaCa-2 and β-TC-6 cells using Lipofectamine 2000. The expression of SSTR5 L335 was determined with a mouse monoclonal anti-SSTR5 L335 antibody generated in our laboratory. The cell proliferation rate was measured by performing MTS assays. Insulin concentration was measured by performing ELISA assays. Results 1. Genotyping of the patients' blood indicated that the frequency of the T allele (CT and TT genotypes) in codon 335 of SSTR5 in Caucasians, Hispanics and African Americans was 52%, 69% and 35%, respectively. Statistical analysis indicated no significant association existed between the frequency of the T allele and the existence of pancreatic cancer in each race. 2. Of the 17 tested human pancreatic cancer cell lines, 5 cell lines (CAPAN-2, HPAF-II, Panc03.27, Panc-1, and -3) had the homozygote TT genotype and 9 cell lines including Mia PaCa-2 were heterozygote (CT genotype). 3. Over-expression of SSTR5 L335 in Mia PaCa-2 cells enhanced cell proliferation compared to over-expression of SSTR5 P335; 4. Over-expression of SSTR5 P335 enhanced the inhibitory effect of SSTR5 agonist RPL-1980 on cell proliferation of Mia PaCa-2 cells and glucose-stimulated insulin secretion from mouse insulinoma cells, while over-expression of SSTR5 L335 blocked the inhibitory effect of RPL-1980. 5. Over-expression of SSTR5 L335 enhanced PDX-1 expression in Mia PaCa-2 cells. Conclusion SSTR5 P335L SNP widely exists in the human population; in patients with pancreatic cancer, which are race-dependent; and in human pancreatic cancer cell lines. In contrast to SSTR5 P335, over-expression of SSTR5 L335 variant resulted in cellular proliferation and PDX-1 over-expression in human pancreas cancer cells and blocked the inhibitory effect of an SSTR5-specific analogue on human pancreas cancer cell proliferation and glucose-stimulated insulin secretion from mouse insulinoma cells. These data suggest that SSTR5 P335L is a hypofunctional protein with a potential harmful effect on function, as well as potential latent effect, and therefore could affect...

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Defining the Cancer Master Switch

et al. 2011

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Defining useful targets for therapy depends on identifying pathways that are crucial for tumor growth, survival, and metastasis. Because not all signaling cascades are created equal, selecting master switches or targets for intervention needs to be done in a systematic fashion. This discussion proposes a set of criteria to define what it means to be a cancer master switch and provides examples to illustrate their application.

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PDX‐1

Cited by 39 publications

References 57 publications

Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.

Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.

The Hypofunctional Effect of P335L Single Nucleotide Polymorphism on SSTR5 Function

Defining the Cancer Master Switch

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