Department of Internal Medicine and Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju 561-712, Korea.
Department of Internal Medicine and Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju 561-712, Korea.
Int J Oncol. 2018 Dec;53(6):2789-2799. doi: 10.3892/ijo.2018.4562. Epub 2018 Sep 14.
TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through death receptors (DRs)4 and/or 5 expressed on the cell surface. Multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to DR4 or DR5. However, their therapeutic potential is limited by the high frequency of cancer resistance. In this study, we provide evidence demonstrating the role of lipocalin 2 (LCN2) in the TRAIL-mediated apoptosis of human colorectal cancer (CRC). By analyzing the mRNA expression data of 71 CRC tissues from patients, we found that DR5 was preferentially expressed in CRC tissues with a low LCN2 expression level compared to tissues with a high LCN2 expression level. Moreover, we analyzed the association between DR5 and LCN2 expression and this analysis revealed that DR5 expression in CRC tended to be inversely associated with LCN2 expression. By contrast, no association was found between the DR4 and LCN2 expression levels. The expression patterns of LCN2 in human CRC cell lines also exhibited an inverse association with DR5 expression. The knockdown of LCN2 by siRNA in the TRAIL‑resistant CRC cells expressing high levels of LCN2 led to a significant increase in TRAIL-induced apoptosis through the upregulation of DR5 protein and mRNA expression. The mechanism through which LCN2 silencing sensitized the CRC cells to TRAIL was dependent on the extrinsic pathway of apoptosis. In addition, we identified that the knockdown of LCN2 enhanced the sensitivity of the cells to TRAIL through the p38 MAPK/CHOP-dependent upregulation of DR5. Taken together, the findings of this study suggest that LCN2 is responsible for TRAIL sensitivity and LCN2 may thus prove to be a promising target protein in DR-targeted CRC therapy.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）通过细胞表面表达的死亡受体（DRs）4 和/或 5 诱导细胞凋亡。目前正在进行多项临床试验，以评估重组人 TRAIL 和 DR4 或 DR5 激动性抗体的抗肿瘤活性。然而，它们的治疗潜力受到癌症耐药性高发的限制。在这项研究中，我们提供了证据表明脂联素 2（LCN2）在 TRAIL 介导的人结直肠癌（CRC）细胞凋亡中的作用。通过分析 71 例 CRC 患者组织的 mRNA 表达数据，我们发现与高 LCN2 表达水平的组织相比，DR5 在 LCN2 低表达水平的 CRC 组织中优先表达。此外，我们分析了 DR5 和 LCN2 表达之间的相关性，分析表明 DR5 在 CRC 中的表达趋势与 LCN2 表达呈负相关。相比之下，在 DR4 和 LCN2 表达水平之间没有发现相关性。LCN2 在人 CRC 细胞系中的表达模式也与 DR5 表达呈负相关。在高表达 LCN2 的 TRAIL 耐药 CRC 细胞中，通过 siRNA 敲低 LCN2 可导致 DR5 蛋白和 mRNA 表达上调，从而显著增加 TRAIL 诱导的细胞凋亡。LCN2 沉默使 CRC 细胞对 TRAIL 敏感的机制依赖于细胞凋亡的外在途径。此外，我们确定 LCN2 敲低通过 p38 MAPK/CHOP 依赖性上调 DR5 增强了细胞对 TRAIL 的敏感性。总之，这项研究的结果表明，LCN2 负责 TRAIL 敏感性，因此 LCN2 可能成为 DR 靶向 CRC 治疗的有前途的靶蛋白。
