Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arachidonic acid metabolism plays an important role in colon carcinogenesis. Cyclooxygenase-2 (COX-2), which catalyzes the rate-limiting step in the synthesis of prostaglandins from arachidonic acids, is known to be up-regulated in colon cancer, and multiple lines of evidence indicate that it is a critical early step in colon carcinogenesis. Recently, 15-lipoxygenase-1, the enzyme that converts arachidonic acid to 15(S)-HETE, was also found to be up-regulated in colon carcinoma. In our previous studies, we cloned a gene that encodes another arachidonic acid-using enzyme, fatty acid CoA ligase 4 (FACL4), and showed that overexpression of this enzyme prevents apoptosis. We have also showed that FACL4 and COX-2 synergistically inhibit apoptosis by reducing the intracellular level of free arachidonic acid. Here, we report that expression of FACL4 is significantly increased in colon adenocarcinoma compared with adjacent normal tissue at both the mRNA and protein levels by quantitative RT-PCR (paired t test, P < 0.015), immunoblot, and immunohistochemical staining. We found that the increase in expression level of FACL4 mRNA relative to control ranged between 2.4- and 54.5-fold; the average fold-increase was 13.4. The increase in FACL4 protein expression is between 2.4- and 65.0-fold. In addition, we found that a higher level of increased FACL4 expression was correlated with well and moderately differentiated adenocarcinoma, whereas no similar correlation was observed with COX-2 expression. The in situ hybridization results indicate that expression of FACL4 is localized predominantly in the colon epithelium but not in the stroma. The onset of FACL4 up-regulation appears to occur during the transformation from adenoma to adenocarcinoma because FACL4 expression was not increased above normal in the three colon adenomas examined. Finally, we observed that a tumor promoter significantly induced FACL4 expression. These findings suggest that the FACL4 pathway may be important in colon carcinogenesis, and that the development of selective inhibitors for FACL4 may be a worthy effort in the prevention and treatment of colon cancer.
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PMID:Fatty acid CoA ligase 4 is up-regulated in colon adenocarcinoma. 1173 23

The alterations in carbohydrate metabolism that fuel tumor growth have been extensively studied. However, other metabolic pathways involved in malignant progression, demand further understanding. Here we describe a metabolic acyl-CoA synthetase/stearoyl-CoA desaturase ACSL/SCD network causing an epithelial-mesenchymal transition (EMT) program that promotes migration and invasion of colon cancer cells. The mesenchymal phenotype produced upon overexpression of these enzymes is reverted through reactivation of AMPK signaling. Furthermore, this network expression correlates with poorer clinical outcome of stage-II colon cancer patients. Finally, combined treatment with chemical inhibitors of ACSL/SCD selectively decreases cancer cell viability without reducing normal cells viability. Thus, ACSL/SCD network stimulates colon cancer progression through conferring increased energetic capacity and invasive and migratory properties to cancer cells, and might represent a new therapeutic opportunity for colon cancer treatment.
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PMID:A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy. 2645 12

An abnormal acyl-CoA synthetase/stearoyl-CoA desaturase (ACSL/SCD) lipid network fuels colon cancer progression, endowing cells with invasive and migratory properties. Therapies against this metabolic network may be useful to improve clinical outcomes. Because micro-RNAs (miRNAs/miRs) are important epigenetic regulators, we investigated novel miRNAs targeting this pro-tumorigenic axis; hence to be used as therapeutic or prognostic miRNAs. Thirty-one putative common miRNAs were predicted to simultaneously target the three enzymes comprising the ACSL/SCD network. Target validation by quantitative RT-PCR, Western blotting, and luciferase assays showed miR-544a, miR-142, and miR-19b-1 as major regulators of the metabolic axis, ACSL/SCD Importantly, lower miR-19b-1 expression was associated with a decreased survival rate in colorectal cancer (CRC) patients, accordingly with ACSL/SCD involvement in patient relapse. Finally, miR-19b-1 regulated the pro-tumorigenic axis, ACSL/SCD, being able to inhibit invasion in colon cancer cells. Because its expression correlated with an increased survival rate in CRC patients, we propose miR-19b-1 as a potential noninvasive biomarker of disease-free survival and a promising therapeutic miRNA in CRC.
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PMID:Targeting the lipid metabolic axis ACSL/SCD in colorectal cancer progression by therapeutic miRNAs: miR-19b-1 role. 2907 7

Modulation of fatty acids metabolism is an appropriate strategy for starvation-induced death in tumor cancers. Colon cancer cells express a high level of acyl-CoA synthetase-5 (ACSL5), and as yet no therapeutic approach has been achieved. Herein, ACSL5-related microRNAs (miRNAs) were identified via TargetScan, and their impacts on ACSL5 and lipid content along with metabolic activity, cell cycle, migration, and invasion of colorectal cancer (CRC) cells were examined, and subsequently compared with transcriptome for better visualization of intracellular-signaling networks. In vivo analysis was performed using BALB/c mice xenograft model of CRC injected with target miRNA. Clinical significances were also evaluated in 80 CRC tumors and matched adjacent normal tissues. There was a reverse correlation between ACSL5 and miR-497-5p, which miR-497-5p overexpression modulated CRC cell proliferation and development. A similar observation was received from the in vivo examination in which intratumoral injection of miR-497-5p reversed the tumor growth in the CRC xenograft model. Downregulation of miR-497-5p correlated with tumor differentiation, tumor, node, and metastasis staging, lymph node metastasis, and poor survival in patients with CRC. These results suggested that miR-497-5p upregulation could be considered as a therapeutic strategy for modulation of lipid metabolism in colon cancer.
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PMID:miR-497-5p mediates starvation-induced death in colon cancer cells by targeting acyl-CoA synthetase-5 and modulation of lipid metabolism. 3201 65