Nguyen Yen Thi-Kim, Moon Jeong Yong, Ediriweera Meran Keshawa, Cho Somi Kim
Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju 63243, Korea.
Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea.
Cancers (Basel). 2020 Jan 22;12(2):268. doi: 10.3390/cancers12020268.
Resistance to chemotherapy and radiation therapy is considered a major therapeutic barrier in breast cancer. Cancer stem cells (CSCs) play a prominent role in chemo and radiotherapy resistance. The established chemo and radio-resistant triple-negative breast cancer (TNBC) cell line MDA-MB-231/IR displays greater CSC characteristics than the parental MDA-MB-231 cells. Escalating evidence demonstrates that metadherin (MTDH) is associated with a number of cancer signaling pathways as well as breast cancer therapy resistance, making it an attractive therapeutic target. Kaplan-Meier plot analysis revealed a correlation between higher levels of MTDH and shorter lifetimes in breast cancer and TNBC patients. Moreover, there was a positive correlation between the MTDH and CD44 expression levels in The Cancer Genome Atlas breast cancer database. We demonstrate that MTDH plays a pivotal role in the regulation of stemness in MDA-MB-231/IR cells. Knockdown of MTDH in MDA-MB-231/IR cells resulted in a reduction in the CSC population, aldehyde dehydrogenase activity, and major CSC markers, including β-catenin, CD44, and Slug. In addition, MTDH knockdown increased reactive oxygen species (ROS) levels in MDA-MB-231/IR cells. We found that phenethyl isothiocyanate (PEITC), a well-known pro-oxidant phytochemical, suppressed stemness in MDA-MB-231/IR cells through ROS modulation via the downregulation of MTDH. Co-treatment of PEITC and N-Acetylcysteine (a ROS scavenger) caused alterations in PEITC induced cell death and CSC markers. Moreover, PEITC regulated MTDH expression at the post-transcriptional level, which was confirmed using cycloheximide, a protein synthesis inhibitor.
对化疗和放疗的耐药性被认为是乳腺癌治疗的主要障碍。癌症干细胞（CSCs）在化疗和放疗耐药中起重要作用。已建立的化疗和放疗耐药三阴性乳腺癌（TNBC）细胞系MDA-MB-231/IR比亲代MDA-MB-231细胞表现出更强的癌症干细胞特征。越来越多的证据表明，黏附素（MTDH）与多种癌症信号通路以及乳腺癌治疗耐药性相关，使其成为一个有吸引力的治疗靶点。Kaplan-Meier生存曲线分析显示，乳腺癌和TNBC患者中MTDH水平较高与生存期较短之间存在相关性。此外，在癌症基因组图谱乳腺癌数据库中，MTDH与CD44表达水平呈正相关。我们证明MTDH在MDA-MB-231/IR细胞干性调节中起关键作用。敲低MDA-MB-231/IR细胞中的MTDH导致癌症干细胞群体、醛脱氢酶活性以及包括β-连环蛋白、CD44和Slug在内的主要癌症干细胞标志物减少。此外，敲低MTDH增加了MDA-MB-231/IR细胞中的活性氧（ROS）水平。我们发现，苯乙基异硫氰酸酯（PEITC）是一种著名的促氧化植物化学物质，通过下调MTDH调节ROS，从而抑制MDA-MB-231/IR细胞的干性。PEITC与N-乙酰半胱氨酸（一种ROS清除剂）联合处理导致PEITC诱导的细胞死亡和癌症干细胞标志物发生改变。此外，PEITC在转录后水平调节MTDH表达，这一结果通过蛋白质合成抑制剂环己酰亚胺得到证实。
