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Expression data from MTDH knockdown in the Hec50co endometrial cancer cell line

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 has recently been implicated in poor clinical outcome in breast cancer, neroblastoma, hepatocellular carcinoma and prostate cancer. In this present study, we focused on the therapeutic benefit of MTDH depletion to restore sensitivity to cell death mediated by a combinatorial therapy of tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL), which promotes death of cancerous cells of the human reproductive tract, and histone deacetylase (HDAC) inhibitors, which have been shown to increase sensitivity of cancer cells to TRAIL-induced apoptosis. Our data indicate that depletion of MTDH in endometrial cancer cells results in sensitization of cells that were previously resistant to cell death mediated by combinatorial treatment with TRAIL and HDAC inhibitor LBH589. MTDH was found to be involved in G2/M checkpoint regulation in response to 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 resistance to combinatorial TRAIL and HDAC inhibitor targeted therapy. Inhibition of PDK1,AKT phosphorylation and increase Bim expression and XIAP degradation may result in sensitivity to cell death induction in MTDH depleted Hec50co cells by TRAIL and LBH 589 combination treatment. These findings indicate that depletion of MTDH is a potentially novel avenue for effective cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26134 | GEO | 2010/12/17

SECONDARY ACCESSION(S): PRJNA135381

REPOSITORIES: GEO

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Project description:Background: TRAIL (TNF-related apoptosis inducing ligand) exhibits selective proapoptotic activity in multiple tumor types, while sparing normal cells. This selectivity makes TRAIL an attractive therapeutic candidate for cancer patients. However, despite encouraging activity in preclinical models, clinical trials with TRAIL mimetics/death receptor agonists demonstrated insufficient activity, largely due to emerging resistance to these agents. Herein, we investigated the cytotoxic activity of a novel, TRAIL-based chimeric protein AD-051.4 combining TRAIL and VEGFA-derived peptide sequences, in hematological malignancies. We characterize key molecular mechanisms leading to resistance and propose rational pharmacological combinations sensitizing cells to AD-051.4. Methods: Sensitivity of DLBCL, classical Hodgkin lymphoma, (cHL), Burkitt lymphoma (BL) and acute myeloid leukemia (AML) to AD-051.4 was assessed in vitro with MTS assay and apoptosis tests (Annexin V/PI staining). Markers of apoptosis were assessed using immunoblotting, flow cytometry, or fluorogenic caspase cleavage assays. Resistant cell lines were obtained by incubation with increasing doses of AD-O51. Transcriptomic analyses were performed by RNA sequencing. Sensitizing effects of selected pathway modulators (BCL2, dynamin and HDAC inhibitors) were assessed using MTS/apoptosis assays. Results: AD-051.4 exhibited low-nanomolar cytotoxic activity in DLBCL cells, but not in other lymphoid or AML cell lines. AD-051.4 induced death-receptor (DR) mediated, caspase-dependent apoptosis in sensitive DLBCL cells, but not in primary resistant cells. The presence of DRs and caspase 8 in cancer cells was crucial for AD-O51.4-driven apoptosis. To understand the potential mechanisms of resistance in an unbiased way, we engineered AD-051.4-resistant cells and evaluated resistance-associated transcriptomic changes. Resistant cells exhibited changes in the expression of multiple genes and pathways associated with apoptosis, endocytosis and HDAC-dependent epigenetic reprogramming, suggesting potential therapeutic strategies of sensitization to AD-051.4. In subsequent analyses, we demonstrated that HDAC inhibitors, BCL2 inhibitors and endocytosis/dynamin inhibitors sensitized primary resistant DLBCL cells to AD-051.4 Conclusions: Taken together, we identified rational pharmacologic strategies sensitizing cells to AD-051.4, including BCL2, histone deacetylase inhibitors and dynamin modulators. Since AD-051.4 exhibits favorable pharmacokinetics and an acceptable safety profile, further clinical development is expected. Identification of resistance mechanisms in a clinical setting might indicate a personalized pharmacological approach to override the resistance.

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Expression data from MTDH knockdown in the Hec50co endometrial cancer cell line

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