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-α-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

Entwicklung ultrakleiner metallischer Tunnelelemente fuer den steuerbaren Einzelelektronentransfer Forschungsbericht/Abschlussbericht

Available from TIB Hannover: F98B100+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Entwicklung ultrakleiner metallischer Tunnelelemente fuer den steuerbaren Einzelelektronentransfer Forschungsbericht/Abschlussbericht

Available from TIB Hannover: F98B100+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Verfahren zur Herstellung eines Duennschichtsystems

DE 10051509 A UPAB: 20020815 NOVELTY - Production of a thin layer system comprises introducing power into the plasma in the form of a controlled number of pulses during deposition of extremely thin layers; and adjusting the average power during the pulse-one time by three times the power averaged over the whole coating time during the deposition of the layer. DETAILED DESCRIPTION - Preferred Features: The average power during the pulse-one time is adjusted by ten times the power averaged over the whole coating time during the deposition of the layer. The power is periodically or aperiodically introduced into the plasma in the form of a controlled number of pulses. USE - Used in the production of magnetic layer systems (claimed), e.g. for storage media, and flat TV screens. ADVANTAGE - The layer system is reproducible