Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylation of the promoter region of tumor suppressor genes may be associated with transcriptional silencing and tumor progression. The 5' region of the TP53 gene does not contain a CpG island, but a basal promoter region of 85 bp is essential for its full promoter activity. In the present study, we assessed whether TP53 promoter methylation is present in malignant glioma cells and whether this is associated with reduced TP53 expression. Methylation-specific PCR revealed TP53 promoter methylation in three (U87MG, LNT-229, T98G) out of six malignant glioma cell lines studied. Treatment with 5-aza-2'-deoxycytidine (5-aza-dC) led to up-regulated expression of TP53 mRNA and protein in U87MG and T98G cells, suggesting that promoter methylation is associated with reduced expression in some malignant glioma cells. We then assessed TP53 promoter methylation in primary tissue of low-grade gliomas, and observed TP53 promoter methylation in 29/48 (60%) low-grade astrocytomas, 11/18 (61%) oligoastrocytomas, and 31/42 (74%) oligodendrogliomas. Promoter methylation of the p14ARF gene, another gene involved in the TP53 pathway, was detected by methylation-specific PCR in 5/49 (10%) low-grade astrocytomas, 7/18 (39%) oligoastrocytomas, and 15/41 (37%) oligodendrogliomas. Our previous and present data show alterations of at least one of TP53 promoter methylation, p14ARF promoter methylation, and TP53 mutations in 43/49 (88%) of low-grade astrocytomas, 15/18 (83%) of oligoastrocytomas, and 35/42 (83%) oligodendrogliomas, suggesting that disruption of the TP53/p14ARF pathway is frequent in all histological types of low-grade glioma.
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PMID:TP53 promoter methylation in human gliomas. 1602 87

Temozolomide (TMZ) is an alkylating chemotherapeutic agent that prolongs the survival of patients with glioblastoma. Clinical benefit is more prominent in patients with methylation of the O(6) -methyl-guanine DNA methyltransferase (MGMT) promoter. However, all patients eventually suffer from tumor progression because their tumors become resistant to TMZ. Here, we modeled acquired TMZ resistance in glioma cells in vitro to identify underlying molecular mechanisms. To this end, the glioma cell lines LNT-229, LN-308, and LN-18 were exposed repetitively to increasing concentrations of TMZ to induce a stable resistant phenotype (R) defined by clonogenic survival assays. The molecular mechanisms mediating acquired resistance were assessed by immunoblot, PCR, and flow cytometry. Rescue experiments were performed with siRNA-mediated candidate gene silencing. We found in LN-18 cells constitutively expressing MGMT a strong up-regulation of MGMT levels in TMZ-resistant cells. TMZ resistance in the MGMT-negative cell lines LNT-229 and LN-308 was not associated with de novo expression of MGMT. Instead, we found a down-regulation of several DNA mismatch-repair proteins in resistant LNT-229 cells. A TMZ-resistant phenotype was also achieved by silencing selected DNA mismatch repair proteins in parental LNT-229 cells. No obvious mechanism of resistance was identified in the third cell line, LN-308, except for reduced methylation of LINE-1 repetitive elements. In conclusion, we demonstrate that different molecular mechanisms may contribute to the development of acquired TMZ resistance in glioma cells, indicating the need to develop distinct strategies to overcome resistance.
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PMID:Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells. 2256 86