Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is one of the major causes of human cancer deaths worldwide. To identify alterations of the genetic program associated with human HCC, we designed a new protocol based on the high-density replica method to analyze protein kinase gene expression in normal liver, HCC, and HCC-derived cell lines. RNA was prepared for reverse transcription and cDNA was used for PCR amplification of the conserved catalytic domain of protein kinase genes. Initially, from a pair of HCC and the adjacent noncancerous tissues, we sequenced 228 samples and identified 26 genes that represent different tyrosine kinase subfamilies. High-density grid filters were then prepared to assist the identification, by hybridization, of genes that are differentially expressed in normal vs HCC samples. Eleven tyrosine kinase genes were tested, and positive signals were reliably scored by doubly offset duplicates and by two independent gene-specific probes. Of the 11 genes tested, PDGF receptor-beta, MEKK-3, axl, and FGFR-4 are preferentially expressed in tumor samples. Additionally, we analyzed protein kinase gene expression in five HCC cell lines and identified distinct kinase gene expression patterns in different cell lines. Our results suggest that multiple kinases are activated in different tumors and confirm that there is molecular heterogeneity in the mechanisms sustaining autonomous cell growth in liver tumor formation.
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PMID:Parallel hybridization analysis of multiple protein kinase genes: identification of gene expression patterns characteristic of human hepatocellular carcinoma. 967 27

Hepatocellular carcinoma (HCC) is a common human malignancy. Its high mortality rate is mainly a result of high intrahepatic recurrence and portal venous invasion (PVI). We previously reported that the development of PVI is related to levels of des-gamma-carboxy prothrombin (DCP), a serum protein that increases at a notably higher rate in patients with HCC. Because DCP is produced by a vitamin K shortage, we examined the biological effects of extrinsic supplementation of vitamin K(2) in HCC cells in vitro and in vivo. Consequently, vitamin K(2) inhibits the growth and invasion of HCC cells through the activation of protein kinase A, which modulates the activities of several transcriptional factors and inhibits the small GTPase Rho, independent of suppression of DCP. In addition, administration of vitamin K(2) to nude mice inoculated with liver tumor cells reduced both tumor growth and body weight loss. In conclusion, similar to an acyclic retinoid--which was previously reported to prevent the recurrence of HCC--vitamin K(2), another lipid-soluble vitamin, may be a promising therapeutic means for the management of HCC.
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PMID:Vitamin K2 inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation. 1523 8

Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide. In light of the very poor 5 year survival new therapeutic approaches are mandatory. Several reports indicate that the epidermal growth factor receptor (EGFR) is expressed frequently in HCC, most likely contributing to the aggressive growth characteristics of these tumors. Cetuximab, a chimeric monoclonal IgG1 antibody directed against the EGFR, potently suppresses the growth of various cancers but its effect on HCC remains to be explored. We therefore studied the antineoplastic potency of cetuximab in human HCC cells alone and in combination with growth factor tyrosine-kinase inhibition (TKI) or HMG-CoA-reductase inhibiton or conventional cytostatics. Cetuximab inhibited growth of p53 wild-type HepG2 hepatocellular cancer cells in a time- and dose-dependent manner. Cetuximab treatment resulted in arresting the cell cycle in the G(1)/G(0)-phase due to an increase of expression of the cyclin-dependent kinase inhibitors p21(Waf1/CIP1) and p27(Kip1) and a decrease in cyclin D1 expression. Additionally, we observed a moderate increase in apoptosis as demonstrated by caspase-3 activation. Combining cetuximab with TKIs (erlotinib or AG1024) or the HMG-CoA-reductase inhibitor fluvastatin or doxorubicin resulted in synergistic antiproliferative effects. In contrast, p53 mutated Huh-7 hepatocellular cancer cells proved to be less sensitive towards cetuximab, but when combined with TKIs or fluvastatin or doxorubicin a pronounced reduction of cell growth was observed. To conclude, our study may provide a rationale for future clinical investigations of cetuximab combination therapy for growth control of hepatocellular cancer.
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PMID:EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular cancer. 1622 26

Hepatocellular carcinoma (HCC) is one of the major malignancies in the world. The prognosis of HCC is poor, due to frequent intrahepatic metastasis and tumor recurrence. P21-activated protein kinase (Pak1), a main downstream effector of small Rho GTPases, Rac1 and Cdc42, plays an important role in the regulation of cell morphogenesis, motility, mitosis, and angiogenesis. Here, we show that Pak1 gene was overexpressed in human HCCs. Overexpression of Pak1 in human HCCs was associated with more aggressive tumor behavior in terms of more metastatic phenotype and more advanced tumor stages. In addition, HCC cell line stably expressing Pak1 displayed increased cell motility rates and, conversely, knockdown of endogenous Pak1 expression by small interfering RNA reduced the migration rates of HCC cells. In an established metastatic HCC cell line, we found that Pak1 was overexpressed compared with its primary HCC cell line and this overexpression was associated with higher cell motility. Importantly, we found that c-Jun NH(2)-terminal kinase (JNK) was activated in HCC cell lines overexpressing Pak1. Inhibition of the JNK activity by chemical inhibitor significantly reduced the migration rates of HCC cells via attenuation of paxillin phosphorylation at Ser(178). In conclusion, our results document that Pak1 is overexpressed in HCCs and plays an important role in the metastasis of HCC. The mechanism by which Pak1 induces cancer metastasis may involve activation of JNK and phosphorylation of paxillin.
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PMID:P21-activated protein kinase is overexpressed in hepatocellular carcinoma and enhances cancer metastasis involving c-Jun NH2-terminal kinase activation and paxillin phosphorylation. 1744 71

Hepatocellular carcinoma has been described to exhibit characteristics similar to that of neuroendocrine tumors (NETs). This includes similar anti-neoplastic responses to extracellular signal-regulated kinase (ERK) activation. NET cells and HepG2 cells have both shown growth inhibition with ERK activation. ZM336372, a Raf-1 activating agent, has been shown to cause growth inhibition and suppression of hormone secretion in a neuroendocrine cell line. Here we examine treatment of the HepG2 cell line with ZM336732 to determine if a similar anti-proliferative response will be obtained. HepG2 cells were treated with ZM336372 or solvent (dimethyl sulfoxide). The resulting effect on the proliferation was measured using the 3,4-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Western blot analysis was performed to examine the activation of the Raf-1/mitogen-activated protein kinase kinase/ERK pathway, chromogranin A production, and p21CIP1 level. Growth inhibition was observed with ZM336372 in a dose-dependent fashion. Minimal baseline phosphorylation of ERK 1/2 was observed; however, activation was observed after treatment with ZM336372. Chromogranin A secretion was suppressed due to treatment with ZM336372. A dose-dependent up-regulation of p21CIP1 was observed in response to ZM336372 treatment. ZM336372 causes growth inhibition, suppression of hormone secretion, and up-regulation of cell cycle inhibitors in a human hepatocellular carcinoma cell line, similar to that previously seen in NETs.
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PMID:ZM336372, a Raf-1 activator, causes suppression of proliferation in a human hepatocellular carcinoma cell line. 1829 43

Hepatocellular carcinoma (HCC) is associated with a historical 5-year survival rate of less than 5%. Evidence suggests that the incidence of HCC is rising in several countries, including the US. Current curative treatment options for HCC include surgical resection and liver transplantation, but these approaches are restricted to carefully selected patients who may benefit from such interventions. Other curative options include ablative therapies, which destroy tumor cells via the injection of chemical substances, radiation, or heating or cooling. Patients with more advanced HCC may be candidates for noncurative treatments, including transarterial embolization and transarterial ablative therapy with beads impregnated with radiation-emitting substances - if the tumor has not invaded vessels or disseminated outside the liver. New therapeutic approaches include Raf kinase inhibitors, such as sorafenib. Other treatments under investigation include immunotherapy, tyrosine kinase receptor inhibitors, and treatments arising from technical advances in ablation and radiation. These new approaches may help to address the enormous need for expanded treatment options for patients with HCC.
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PMID:Hepatocellular carcinoma (HCC): current and evolving therapies. 1831 57

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, causing 500,000 deaths yearly. The risk factors mostly responsible for the rising incidence of HCC in the Western hemisphere are hepatitis C, alcoholic cirrhosis, and nonalcoholic steatohepatitis, which most commonly leads to HCC in the setting of cirrhosis. Over the past 30 years, several chemotherapeutic single agents and combinations have been tested in HCC, yet none have demonstrated any improvement in survival. Recently, the multitargeted anti-angiogenic and Raf kinase inhibitor sorafenib has shown a survival advantage as a single agent and improved outcomes in combination with doxorubicin. Other novel agents have also shown intriguing outcomes as single agents (sunitinib) or in combination (bevacizumab and erlotinib). The encouraging results and clinical information gathered in recent trials are generating important clinical questions regarding which patients to treat, how to accommodate concurrent cirrhosis, and which parameters to use to monitor efficacy and the potential benefit from therapy.
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PMID:The impact of new data in the treatment of advanced hepatocellular carcinoma. 1876 49

Hepatocellular carcinoma (HCC) displays a striking resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Therefore, the characterization of pharmacological agents that overcome this resistance may provide new therapeutic modalities for HCC. Here, we examined whether glycogen synthase kinase-3 (GSK-3) inhibitors could restore TRAIL sensitivity in hepatoma cells. To this aim, the effects of two GSK-3 inhibitors, lithium and SB-415286, were analyzed on TRAIL apoptotic signaling in human hepatoma cell lines in comparison with normal hepatocytes. We observed that both inhibitors sensitized hepatoma cells, but not normal hepatocytes, to TRAIL-induced apoptosis by enhancing caspase-8 activity and the downstream recruitment of the mitochondrial machinery. GSK-3 inhibitors also stabilized p53 and the down-regulation of p53 by RNA interference abolished the sensitizing effect of lithium on caspase-3 activation. Concomitantly, GSK-3 inhibitors strongly activated c-Jun N-terminal kinases (JNKs). The pharmacological inhibition of JNKs with AS601245 or SP600125 resulted in an earlier and stronger induction of apoptosis indicating that activated JNKs transduced protective signals and provided an anti-apoptotic balance to the pro-apoptotic effects of GSK-3 inhibitors. These findings demonstrate that GSK-3 exerts a negative and complex constraint on TRAIL apoptotic signaling in hepatoma cells, which can be greatly alleviated by GSK-3 inhibitors. Therefore, GSK-3 inhibitors may open new perspectives to enhance the anti-tumor activity of TRAIL in HCC.
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PMID:Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells. 1893 43

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer deaths. Surgical resection, with or without transplantation, can result in long-term survival. However, surgery can only be performed in about 15% of patients with HCC and the 5-year survival rate is only approximately 33%-50% after potentially curative resection. Percutaneous ethanol injection, radiofrequency ablation, and transarterial chemoembolization are invasive techniques that have shown efficacy in reducing tumor bulk. Similarly, systemic chemotherapy may induce tumor responses, but a survival benefit has not been clearly demonstrated. In addition, the lack of efficacy of antiandrogens, tamoxifen, and single-agent interferon has now been confirmed.Sorafenib is a multikinase inhibitor with antiangiogenic, proapoptotic, and Raf kinase inhibitory activity. In a large, multicenter, randomized, phase 3 trial there was a significant improvement in both time to disease progression and overall survival with sorafenib compared with placebo. Sorafenib is the first agent to demonstrate a consistent improvement in overall survival for patients with advanced HCC. Further studies are required to determine the role of other molecular-targeted therapies, either alone or in combination with sorafenib in patients with advanced HCC. Further studies are also required to determine the role of sorafenib in combination with locoregional therapies (eg, transarterial chemoembolization), and the role of sorafenib as adjuvant therapy following surgery.
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PMID:Systemic therapy of hepatocellular carcinoma: are we making progress? 1897 75

Hepatocellular carcinoma (HCC) accounts for 6% of all cancers worldwide. In the United States, the incidence is expected to increase due to the increased rate of hepatitis C viral infection affecting that region. Other factors that will influence higher incidence rates for HCC include the persistent presence of alcoholic cirrhosis and the recently recognized correlation between non-alcoholic steatohepatitis (NASH) and HCC. In most cases, cirrhosis is an integral part of the morbidity and mortality associated with HCC, and must be accounted for in order to manage patients with HCC properly. Historically, medical oncologists used the Child-Pugh scoring system of cirrhosis. However, Child-Pugh only categorizes the cirrhosis and does not address factors intrinsic to the cancer itself, which is recognized as a major limitation of that system. The idea of incorporating cancer-related parameters was developed by several research groups. The Cancer of the Liver Italian Program (CLIP) score and the Chinese University Prognostic Index (CUPI) are among many others that were developed and are of great use for patients with hepatitis C- and hepatitis B-associated HCC, respectively. Many chemotherapeutic agents have been tested in HCC, with reported response rates between 10% and 15% and no demonstrated survival advantage. Over the past decade, several molecular targets involved in the etiology of HCC have been identified. Recently, sorafenib, an antiangiogenic and Raf kinase inhibitor, has shown a survival advantage. The innovative therapeutic outcomes associated with novel targeted therapies illustrates the need for biologic and pharmacokinetic end points to define their optimal doses and therapeutic effects.
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PMID:Current management of advanced hepatocellular carcinoma. 1925 98


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