Department of Obstetrics and Gynecology, The University of Iowa, Iowa City, Iowa, United States of America.
PLoS One. 2011;6(6):e20920. doi: 10.1371/journal.pone.0020920. Epub 2011 Jun 8.
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.
了解化疗耐药的分子基础对于设计恢复化疗敏感性的治疗方法至关重要。特别是，已经证明 metadherin (MTDH) 在化疗耐药中起着关键作用。MTDH 的过表达与乳腺癌、神经母细胞瘤、肝细胞癌和前列腺癌的不良临床预后相关。MTDH 在晚期子宫内膜癌中也高度表达，这种疾病迫切需要新的治疗方法。在本研究中，我们专注于 MTDH 耗尽对子宫内膜癌细胞恢复对细胞死亡敏感性的治疗益处，以恢复对细胞死亡的敏感性。细胞用肿瘤坏死因子-α相关凋亡诱导配体（TRAIL）和组蛋白去乙酰化酶（HDAC）抑制剂联合处理，TRAIL 促进人类生殖道恶性细胞死亡，而 HDAC 抑制剂已被证明增加癌细胞对 TRAIL 诱导的凋亡的敏感性。我们的数据表明，MTDH 耗尽可使先前对 TRAIL 和 HDAC 抑制剂 LBH589 联合治疗耐药的子宫内膜癌细胞敏感。MTDH 敲低减少了单独用 LBH589 或 LBH589 联合 TRAIL 处理的细胞中 S 期细胞的比例，并增加了细胞在 G2/M 期的阻滞，表明 MTDH 在细胞周期检查点发挥作用以实现耐药性。使用微阵列技术，我们鉴定了 MTDH 的 57 个下游靶基因，包括钙结合蛋白 1 和半乳糖凝集素 1，它们可能有助于 MTDH 介导的治疗耐药性。另一方面，在 MTDH 耗尽的细胞中，抑制 PDK1 和 AKT 磷酸化以及增加 Bim 表达和 XIAP 降解与 TRAIL 和 LBH589 诱导的细胞死亡敏感性增强相关。这些发现表明，靶向或耗尽 MTDH 可能是逆转子宫内膜癌患者治疗耐药性的一种新途径。
