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.
Highlights
A common problem with cancer therapy is the development of resistance, and an improved understanding of the underlying pathways involved with drug resistance could lead to the development of new strategies to overcome this resistance
MTDH expression is elevated in endometrial cancer cell lines and tissues
The expression of 80 kDa MTDH and putative 50–55 kDa MTDH isoforms were significantly higher in endometrial cancer samples including papillary serous, sarcoma, and adenocarcinoma, whereas MTDH was undetectable in normal endometrial tissues (Figure 1B)
Summary
A common problem with cancer therapy is the development of resistance, and an improved understanding of the underlying pathways involved with drug resistance could lead to the development of new strategies to overcome this resistance. A recently discovered gene, metadherin (MTDH, known as AEG-1 or LYRIC) has emerged as a potentially crucial mediator of tumor progression, metastasis, and resistance to chemotherapies [1,2,3,4]. MTDH is proposed to promote tumor progression through the integration of multiple signaling pathways including ras, myc, Wnt, PI3K/AKT, and NF-kB in various types of cancer cells [4,5,6,7], though the mechanism by which MTDH controls these signaling events is unclear. We investigated the role of MTDH in endometrial cancer and its inhibition as a mechanism to overcome drug resistance. An earlier study reported that lymph node metastasis is significantly associated with copy number gains at 8q22–q23 in endometrial cancers [9]. The ability of MTDH knockdown to sensitize cells to targeted therapies, which have come to symbolize the future of cancer therapeutics, has not yet been explored
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