title: Knockdown of MTDH sensitizes endometrial cancer cells to cell death induction by death receptor ligand TRAIL and HDAC inhibitor LBH589 co-treatment.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, The University of Iowa, Iowa City, Iowa, United States of America. xiangbing-meng@uiowa.edu
authors.forename: Xiangbing
authors.initials: X
authors.lastname: Meng
authors.forename: Pavla
authors.initials: P
authors.lastname: Brachova
authors.forename: Shujie
authors.initials: S
authors.lastname: Yang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xiong
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kristina W
authors.initials: KW
authors.lastname: Thiel
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Leslie
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004347:Drug Interactions; D016889:Endometrial Neoplasms / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D008565:Membrane Proteins; D000077767:Panobinostat; D016601:RNA-Binding Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D015815:Cell Adhesion Molecules; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077767:Panobinostat