20 research outputs found
Knockdown of MTDH Sensitizes Endometrial Cancer Cells to Cell Death Induction by Death Receptor Ligand TRAIL and HDAC Inhibitor LBH589 Co-Treatment
Understanding the molecular underpinnings of chemoresistance is vital to design therapies to restore chemosensitivity. In particular, metadherin (MTDH) has been demonstrated to have a critical role in chemoresistance. Over-expression of MTDH correlates with poor clinical outcome in breast cancer, neuroblastoma, hepatocellular carcinoma and prostate cancer. MTDH is also highly expressed in advanced endometrial cancers, a disease for which new therapies are urgently needed. In this present study, we focused on the therapeutic benefit of MTDH depletion in endometrial cancer cells to restore sensitivity to cell death. Cells were treated with a combination of tumor necrosis factor-Ξ±-related apoptosis-inducing ligand (TRAIL), which promotes death of malignant cells of the human reproductive tract, and histone deacetylase (HDAC) inhibitors, which have been shown to increase the sensitivity of cancer cells to TRAIL-induced apoptosis. Our data indicate that depletion of MTDH in endometrial cancer cells resulted in sensitization of cells that were previously resistant in response to combinatorial treatment with TRAIL and the HDAC inhibitor LBH589. MTDH knockdown reduced the proportion of cells in S and increased cell arrest in G2/M in cells treated with LBH589 alone or LBH589 in combination with TRAIL, suggesting that MTDH functions at the cell cycle checkpoint to accomplish resistance. Using microarray technology, we identified 57 downstream target genes of MTDH, including calbindin 1 and galectin-1, which may contribute to MTDH-mediated therapeutic resistance. On the other hand, in MTDH depleted cells, inhibition of PDK1 and AKT phosphorylation along with increased Bim expression and XIAP degradation correlated with enhanced sensitivity to cell death in response to TRAIL and LBH589. These findings indicate that targeting or depleting MTDH is a potentially novel avenue for reversing therapeutic resistance in patients with endometrial cancer
Inositol Pyrophosphate Profiling of Two HCT116 Cell Lines Uncovers Variation in InsP8 Levels
IP6K structure and the molecular determinants of catalytic specificity in an inositol phosphate kinase family
Association between Polymorphisms of the IL-23R Gene and Allergic Rhinitis in a Chinese Han Population
Genes controlling low phytic acid in plants: Identifying targets for barley breeding
Phytic acid (myo-inositol 1, 2, 3, 4, 5, 6-hexakisphosphate) is the most abundant form of phosphorus in plant seeds. It is indigestible by both humans and nonruminant livestock and can contribute to human mineral deficiencies. The degradation of phytic acid in animal diets is necessary to overcome both environmental and nutritional issues. The development of plant cultivars with low phytic acid content is therefore an important priority. More than 25 low-phytic acid mutants have been developed in rice, maize, soybean, barley, wheat, and bean, from which 11 genes, belonging to six gene families, have been isolated and sequenced from maize, soybean, rice, and Arabidopsis. Forty-one members of the six gene families were identified in the rice genome sequence. A survey of genes coding for enzymes involved in the synthesis of phytic acid identified candidate genes for the six barley mutants with low phytic acid through comparison with syntenic regions in sequenced genomes