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.

Knockdown of astrocyte elevated gene-1 (AEG-1) in cervical cancer cells decreases their invasiveness, epithelial to mesenchymal transition, and chemoresistance

“…This finding is consistent with a previous study that showed knockdown of AEG-1 could decrease the colony formation in SiHa cells. 36 Furthermore, that AEG-1 knockdown led to reduced NF-kB expression (Fig. 4C) is also consistent with our previous finding that NF-κB played important roles in more quiescent cancer stem-like cells than in the bulk cells.…”

Cytoplasmic Metadherin (MTDH) Provides Survival Advantage under Conditions of Stress by Acting as RNA-binding Protein

“…Third, MTDH was shown to co-localize with the RNAinduced silencing complex (RISC) component staphylococcal nuclease domain-containing-1 (SND1) (20,21). Finally, we recently reported that depletion of MTDH alters expression of several MTDH downstream genes, and MTDH is mainly cytoplasmic in the endometrial cancer cell lines used in this study (14).…”

“…Colony Formation-Stable MTDH or control shRNA Hec50 cells were established as reported previously (14). Cells were treated with mitomycin C (MMC) for 24 h and then cultured in normal medium for 2 weeks.…”

Tumor suppressive microRNA-375 regulates lactate dehydrogenase B in maxillary sinus squamous cell carcinoma

“…Many studies have indicated that AEG-1/MTDH contributes to several steps in human oncogenesis, including cancer cell progression, invasion, metastasis, and chemoresistance (39). It is reported that overexpression of AEG-1/ MTDH promotes activation of the pro-survival pathway of PI3K/AKT via up-regulation of PIP3 (40). These facts suggest that miR-375 is a direct regulator of the YWHAZ/14-3-3ζ and AEG-1/MTDH oncogenes, and that this phenomenon is important to HNSCC and MSSCC oncogenesis.…”