Growth dependency of a new human pancreatic cancer cell line, YAPC, on autocrine interleukin-1α stimulation

Yamada, Takayuki; Okajima, Fumikazu; Adachi, Masakazu; Ohwada, Susumu; Kondo, Yoichi

doi:10.1002/(sici)1097-0215(19980330)76:1<141::aid-ijc22>3.0.co;2-e

Cited by 13 publications

(9 citation statements)

References 18 publications

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“…Focal genomic amplification of PAK1 has been reported for several tumour indications . Although PAK1 copy number alteration is infrequent in pancreatic adenocarcinoma, YAPC cells have focal, high‐level amplification of PAK1 (Figure A) and provide an interesting model to examine MET signalling in the context of direct dysregulation of PAK1 by the tumour . An analysis of HGF/MET and PAK1 signalling was performed using exogenous HGF, onartuzumab, and PAK1 knockdown (Figure B) to demonstrate that combined PAK1 and MET inhibition decreased phosphorylation of c‐Jun and STAT3 at sites required for transactivation of these transcription factors (Figure B, lanes 13–16).…”

Section: Resultsmentioning

confidence: 99%

PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition

Zhou¹,

Jubb²,

Lyle³

et al. 2014

The Journal of Pathology

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Pancreatic adenocarcinoma (PDAC) is a major unmet medical need and a deeper understanding of molecular drivers is needed to advance therapeutic options for patients. We report here that p21-activated kinase 1 (PAK1) is a central node in PDAC cells downstream of multiple growth factor signalling pathways, including hepatocyte growth factor (HGF) and MET receptor tyrosine kinase. PAK1 inhibition blocks signalling to cytoskeletal effectors and tumour cell motility driven by HGF/MET. MET antagonists, such as onartuzumab and crizotinib, are currently in clinical development. Given that even highly effective therapies have resistance mechanisms, we show that combination with PAK1 inhibition overcomes potential resistance mechanisms mediated either by activation of parallel growth factor pathways or by direct amplification of PAK1. Inhibition of PAK1 attenuated in vivo tumour growth and metastasis in a model of pancreatic adenocarcinoma. In human tissues, PAK1 is highly expressed in a proportion of PDACs (33% IHC score 2 or 3; n = 304) and its expression is significantly associated with MET positivity (p < 0.0001) and linked to a widespread metastatic pattern in patients (p = 0.067). Taken together, our results provide evidence for a functional role of MET/PAK1 signalling in pancreatic adenocarcinoma and support further characterization of therapeutic inhibitors in this indication.

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Section: Resultsmentioning

confidence: 99%

PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition

Zhou¹,

Jubb²,

Lyle³

et al. 2014

The Journal of Pathology

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“…Establishment of a Highly Peritoneal Metastatic Pancreatic Cancer Cell Line, YAPC-PD-A human pancreatic cancer cell line, YAPC-PD, was established from YAPC cells, which had been previously established in our laboratory (33). The YAPC is not a highly peritoneal metastatic cell line, but, in one nude mouse of 30, which were injected in the peritoneal cavity with YAPC cells (1 ϫ 10 7 per mouse), peritoneal dissemination with bloody ascites was detected 12 weeks after the injection.…”

Section: Materials-1-oleoyl-sn-glycero-3-phosphate (Lpa)mentioning

confidence: 99%

“…Cell Adhesion Assay-Cells were harvested by trypsin, seeded on 48-well plates at a density of 5 ϫ 10 4 cells per well in RPMI 1640 containing 0.1% BSA and test agents, and then incubated for 1 or 4 h. At each time, floating cells were aspirated, plates were rinsed with phosphate-buffered saline, and the attached cells were then evaluated by an 3-(4,5-dimethythiazol-2-yl)-diphenyltetrazolium bromide assay as described previously (33).…”

Section: Materials-1-oleoyl-sn-glycero-3-phosphate (Lpa)mentioning

confidence: 99%

“…Twenty-four hours before the experiments, the medium was changed to RPMI 1640 containing 0.1% BSA, and cells were exposed to the test agents for an additional 24 h. Cell proliferation was evaluated by an 3-(4,5-dimethythiazol-2-yl)-diphenyltetrazolium bromide assay (33). Quantitative Reverse Transcriptase-PCR Using Real-time TaqMan Technology-Total RNA was isolated using Tri-Reagent (Sigma) according to the instructions from the manufacturer.…”

Section: Materials-1-oleoyl-sn-glycero-3-phosphate (Lpa)mentioning

confidence: 99%

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Lysophosphatidic Acid (LPA) in Malignant Ascites Stimulates Motility of Human Pancreatic Cancer Cells through LPA1

Yamada

Sato

Komachi

et al. 2004

Journal of Biological Chemistry

Self Cite

162

153

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Cytokines and growth factors in malignant ascites are thought to modulate a variety of cellular activities of cancer cells and normal host cells. The motility of cancer cells is an especially important activity for invasion and metastasis. Here, we examined the components in ascites, which are responsible for cell motility, from patients and cancer cell-injected mice. Ascites remarkably stimulated the migration of pancreatic cancer cells. This response was inhibited or abolished by pertussis toxin, monoglyceride lipase, an enzyme hydrolyzing lysophosphatidic acid (LPA), and Ki16425 and VPC12249, antagonists for LPA receptors (LPA 1 and LPA 3 ), but not by an LPA 3 -selective antagonist. These agents also inhibited the response to LPA but not to the epidermal growth factor. In malignant ascites, LPA is present at a high level, which can explain the migration activity, and the fractionation study of ascites by lipid extraction and subsequent thin-layer chromatography indicated LPA as an active component. A significant level of LPA 1 receptor mRNA is expressed in pancreatic cancer cells with high migration activity to ascites but not in cells with low migration activity. Small interfering RNA against LPA 1 receptors specifically inhibited the receptor mRNA expression and abolished the migration response to ascites. These results suggest that LPA is a critical component of ascites for the motility of pancreatic cancer cells and LPA 1 receptors may mediate this activity. LPA receptor antagonists including Ki16425 are potential therapeutic drugs against the migration and invasion of cancer cells.

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“…(9,10) IL-8 expression has been found in various human cancers, including human pancreatic cancers. (5)(6)(7)(8)(10)(11)(12)(13) However, our systematic investigation has revealed that IL-8 is overexpressed in most human pancreatic cancer tissues and established cell lines. Additionally, the IL-8 expression level appeared to correlate with its tumorigenic and metastatic potential in an orthotopic xenograft model.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Interleukin-8 Expression by Nitric Oxide in Human Pancreatic Adenocarcinoma

Xiong

Shi

Xin

et al. 2001

Journal of Interferon & Cytokine Research

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The regulation of interleukin-8 (IL-8) expression by nitric oxide (NO) was determined in human pancreatic cancer cell lines. CaPan-2 and FG human pancreatic adenocarcinoma cells were incubated for 24 h in medium alone or medium containing a cytokine mixture in the presence or absence of an NO synthase (NOS) inhibitor, N(G)-monomethyl-L-arginine (NMA). The NOS activity and level of IL-8 expression were determined. IL-8 expression was induced in the two cell lines. A low level of NOS activity was detectable only in CaPan-2 cells. Moreover, the presence of NMA did not reverse the induction of IL-8. The FG cells were then engineered to produce a physiologic level of NO and incubated in medium alone or medium containing 1 mM NMA. No significant IL-8 expression was induced in those producing a low level of NO, whereas IL-8 expression was induced in those producing a high level of NO. Inhibition of NO production by NMA reversed this effect. Incubation of FG cells with an NO donor, S-nitroso-D,L.-acetyl-penicillamine (SNAP), led to a concentration-dependent and time-dependent induction of IL-8 expression. This NO-mediated upregulation of IL-8 expression correlated with an increase in IL-8 gene transcription and mRNA stability. Our results indicate that NO is involved in the regulation of IL-8 expression in and contributes to the progression of human pancreatic cancer.

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Growth dependency of a new human pancreatic cancer cell line, YAPC, on autocrine interleukin-1α stimulation

Cited by 13 publications

References 18 publications

PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition

PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition

Lysophosphatidic Acid (LPA) in Malignant Ascites Stimulates Motility of Human Pancreatic Cancer Cells through LPA1

Regulation of Interleukin-8 Expression by Nitric Oxide in Human Pancreatic Adenocarcinoma

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