Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic carcinoma is characterized by poor prognosis and lack of response to conventional therapy. The reasons for this are not fully understood. We have reported that inhibition of 5-lipoxygenase abolished proliferation and induced apoptosis in pancreatic cancer cells while the 5-lipoxygenase metabolite, 5(S)-hydroxyeicosatetraenoic acid [5(S)-HETE] stimulated pancreatic cancer cell proliferation. The current study was designed to investigate the underlying mechanisms for 5(S)-HETE-stimulated proliferation of pancreatic cells. Two human pancreatic cancer cell lines, PANC-1 and HPAF, were used. Cell proliferation was monitored by thymidine incorporation and cell counting. Phosphorylation of P42/44(MAPK) (mitogen activated protein kinase, ERK), MEK (MAPK/ERK kinase), P38 kinase, JNK/SAPK (c-Jun N-terminal kinase/ stress-activated protein kinase), AKT and tyrosine residues of intracellular proteins was measured by Western blot using their corresponding phospho-specific antibodies. The results showed that (1) 5(S)-HETE markedly stimulated pancreatic cancer cell proliferation in a time- and concentration-dependent manner; (2) 5(S)-HETE induced tyrosine phosphorylation of multiple intracellular proteins while the tyrosine kinase inhibitor, genestein, blocked 5(S)-HETE-stimulated cell proliferation; (3) 5(S)-HETE significantly stimulated both MEK and P42/44(MAPK) phosphorylation and the MEK inhibitors, PD098059 and U0126, inhibited 5(S)-HETE-stimulated proliferation in these two cell lines; (4) 5(S)-HETE also stimulated P38 kinase phosphorylation but the P38 inhibitor, SB203580, did not effect 5(S)-HETE-stimulated cell proliferation; (5) 5(S)-HETE markedly stimulated AKT phosphorylation while the phosphatidylinositide-3 (PI3)-kinase inhibitor, wortmannin, blocked 5(S)-HETE-stimulated cell proliferation; (6) phosphorylation of JNK/SAPK was not induced by 5(S)-HETE, and (7) the general protein kinase C (PKC) inhibitor, GF109203X, did not affect 5(S)-HETE-stimulated cancer cell proliferation. These findings suggest that intracellular tyrosine kinases, MEK/ERK and PI3 kinase/AKT pathways are involved in 5(S)-HETE-stimulated pancreatic cancer cell proliferation but P38 kinase, JNK/SAPK and PKC are not involved in this mitogenic effect.
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PMID:Multiple signal pathways are involved in the mitogenic effect of 5(S)-HETE in human pancreatic cancer. 1470 47

Pancreatic carcinoma is one of the leading causes of cancer mortality worldwide, although the molecular mechanisms of this disease are poorly understood. The aim of this study was to examine the expression of cyclin-dependent kinase inhibitors (CDKIs) and the epigenetic modifications in the promoters of these genes. We also evaluated the correlation between the methylation status of CDKI genes and smoking habit in clinical pancreatic carcinoma specimens. Western blotting and real-time PCR were performed to assess CDKI expression. Methylation-specific PCR was carried out to examine the methylation status of the promoters of CDKI genes. In this study, we revealed that reduced levels of the CDKI proteins, p15INK4b, p16INK4a, p21cip1 and p27kip1, are a prominent feature of pancreatic carcinoma patients. The DNA hypermethylation of the promoter was observed in 40% (2 of 5) of the p15INK4b genes, 60% (3 of 5) of the p16INK4a genes and 60% of the p21cip1 genes, which markedly correlated with their decreased mRNA expression. No hypermethylation was detected in the p27kip1 gene promoter in 5 pancreatic carcinoma patients with markedly decreased expression of p27kip1 mRNA, suggesting an alternative mechanism of p27kip in these patients. In this study, patients with a smoking habit displayed methylation of 2 CDKI genes in their pancreatic carcinoma specimens. We concluded that epigenetic modification via hypermethylation represents a critical mechanism for the inactivation of CDKI genes in pancreatic carcinoma.
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PMID:Reduced levels of p15INK4b, p16INK4a, p21cip1 and p27kip1 in pancreatic carcinoma. 2229 50

Pancreatic carcinoma (PC) is an aggressive malignancy with one of the poorest mortality rates. It is the sixth leading cause of mortality from malignant disease in China and the fourth leading cause of cancer-related mortality in the United States. The poor outcome reflects the requirement for an improved understanding of the transcriptional control of oncogenic signaling pathways. 3-phosphoinositide-dependent protein kinase-1 (PDK1) is a potent oncogenic driver of PC. The present study aimed to elucidate the transcriptional regulation of microRNA (miR)-375-targeted PDK1. miR-375 is a putative target and, in the present study, was observed to be significantly downregulated in the tumor compared with non-tumor tissues from patients with PC (n=44). As determined by a luciferase reporter assay, the ectopic expression of miR-375 was identified to diminish the transcriptional activity of PDK1. Furthermore, immunoblotting revealed that miR-375 suppressed endogenous PDK1 protein levels. Functional assays showed that miR-375 was able to inhibit proliferation and promote apoptosis of the PC cells. miR-375 is a significant regulator of the PDK1 oncogene, suggesting that it may have a potential therapeutic role in the treatment of PC.
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PMID:MicroRNA-375 targets the 3-phosphoinositide-dependent protein kinase-1 gene in pancreatic carcinoma. 2413 44

Pancreatic carcinoma (PC) is a deadly form of cancer with poor overall survival. Currently, chemotherapy such as gemcitabine and 5-fluorouracil (5-FU) are the most popular medications that can improve survival, but rapid drug-resistance makes the search for more effective drugs urgent. Upon looking for natural components to treat PC, it was found that arenobufagin, a cardiac glycosides-like compound, showed significant effects on the gemcitabine-resistant pancreatic carcinoma cell line Panc-1 and the gemcitabine-sensitive cell line ASPC-1 at nanomolar concentrations. The present study used MTT and clonogenic survival assays to examine survival and proliferation, and western blotting to assess changes in the associated mitogen activated protein kinase and phosphoinositide 3-kinase pathways and expression of apoptosis-related proteins. The current study also detected the cell cycle by flow cytometry. Arenobufagin inhibited cell survival and proliferation, decreased the phosphorylation of key downstream proteins of K-Ras, including protein kinase B and extracellular signal related kinase, induced cell cycle G2/M phase arrest and apoptosis, and downregulated the level of phosphorylated epidermal growth factor receptor. Notably, the present data also showed that arenobufagin can enhance the sensitivity of PC cells to gemcitabine and 5-FU. In conclusion, arenobufagin could enhance the effect of gemcitabine and 5-FU on PC cells by targeting multiple key proteins. Therefore, arenobufagin has potential as anadjuvant therapy for the treatment of PC.
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PMID:Effect of arenobufagin on human pancreatic carcinoma cells. 2908 9