Toden Shusuke, Okugawa Yoshinaga, Jascur Thomas, Wodarz Dominik, Komarova Natalia L, Buhrmann Constanze, Shakibaei Mehdi, Boland C Richard, Goel Ajay
Center for Gastrointestinal Research, and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246, USA, Department of Ecology and Evolution and Department of Mathematics, University of California, Irvine, CA, USA and Institute of Anatomy, Ludwig-Maximilian University, Munich, Germany.
Department of Ecology and Evolution and Department of Mathematics, University of California, Irvine, CA, USA and.
Carcinogenesis. 2015 Mar;36(3):355-67. doi: 10.1093/carcin/bgv006. Epub 2015 Feb 4.
Resistance to cytotoxic chemotherapy is a major cause of mortality in colorectal cancer (CRC) patients. Chemoresistance has been linked primarily to a subset of cancer cells undergoing epithelial-mesenchymal transition (EMT). Curcumin, a botanical with antitumorigenic properties, has been shown to enhance sensitivity of cancer cells to chemotherapeutic drugs, but the molecular mechanisms underlying this phenomenon remain unclear. Effects of curcumin and 5-fluorouracil (5FU) individually, and in combination, were examined in parental and 5FU resistant (5FUR) cell lines. We performed a series of growth proliferation and apoptosis assays in 2D and 3D cell cultures. Furthermore, we identified and analyzed the expression pattern of a subset of putative EMT-suppressive microRNAs (miRNAs) and their downstream target genes regulated by curcumin. Chemosensitizing effects of curcumin were validated in a xenograft mouse model. Combined treatment with curcumin and 5FU enhanced cellular apoptosis and inhibited proliferation in both parental and 5FUR cells, whereas 5FU alone was ineffective in 5FUR cells. A group of EMT-suppressive miRNAs were upregulated by curcumin treatment in 5FUR cells. Curcumin suppressed EMT in 5FUR cells by downregulating BMI1, SUZ12 and EZH2 transcripts, key mediators of cancer stemness-related polycomb repressive complex subunits. Using a xenograft and mathematical models, we further demonstrated that curcumin sensitized 5FU to suppress tumor growth. We provide novel mechanistic evidence for curcumin-mediated sensitization to 5FU-related chemoresistance through suppression of EMT in 5FUR cells via upregulation of EMT-suppressive miRNAs. This study highlights the potential therapeutic usefulness of curcumin as an adjunct in patients with chemoresistant advanced CRC.
对细胞毒性化疗的耐药性是结直肠癌（CRC）患者死亡的主要原因。化疗耐药性主要与经历上皮-间质转化（EMT）的癌细胞亚群有关。姜黄素是一种具有抗肿瘤特性的植物提取物，已被证明可增强癌细胞对化疗药物的敏感性，但其潜在分子机制仍不清楚。我们在亲本细胞系和5-氟尿嘧啶耐药（5FUR）细胞系中研究了姜黄素和5-氟尿嘧啶（5FU）单独及联合使用的效果。我们在二维和三维细胞培养中进行了一系列生长增殖和凋亡检测。此外，我们鉴定并分析了一组假定的EMT抑制性微小RNA（miRNA）及其受姜黄素调控的下游靶基因的表达模式。姜黄素的化学增敏作用在异种移植小鼠模型中得到验证。姜黄素与5FU联合治疗可增强亲本细胞和5FUR细胞的细胞凋亡并抑制增殖，而单独使用5FU对5FUR细胞无效。姜黄素处理可使5FUR细胞中一组EMT抑制性miRNA上调。姜黄素通过下调BMI1、SUZ12和EZH2转录本（癌症干性相关多梳抑制复合物亚基的关键介质）来抑制5FUR细胞中的EMT。通过异种移植和数学模型，我们进一步证明姜黄素使5FU对肿瘤生长的抑制作用敏感化。我们通过上调EMT抑制性miRNA抑制5FUR细胞中的EMT，为姜黄素介导的对5FU相关化疗耐药性的增敏作用提供了新的机制证据。本研究强调了姜黄素作为化学耐药性晚期CRC患者辅助治疗药物的潜在治疗价值。
