Lu Haiquan, Chen Ivan, Shimoda Larissa A, Park Youngrok, Zhang Chuanzhao, Tran Linh, Zhang Huimin, Semenza Gregg L
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell Rep. 2017 Feb 21;18(8):1946-1957. doi: 10.1016/j.celrep.2017.02.001.
Breast cancer stem cells (BCSCs) play a critical role in tumor recurrence and metastasis. Exposure of breast cancer cells to chemotherapy leads to an enrichment of BCSCs. Here, we find that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), which is dependent on hypoxia-inducible factor 1 (HIF-1) and HIF-2. Knockdown of GSTO1 expression abrogates carboplatin-induced BCSC enrichment, decreases tumor initiation and metastatic capacity, and delays tumor recurrence after chemotherapy. GSTO1 interacts with the ryanodine receptor RYR1 and promotes calcium release from the endoplasmic reticulum. Increased cytosolic calcium levels activate PYK2 → SRC → STAT3 signaling, leading to increased expression of pluripotency factors and BCSC enrichment. HIF inhibition blocks chemotherapy-induced GSTO1 expression and BCSC enrichment. Combining HIF inhibitors with chemotherapy may improve clinical outcome in breast cancer.
乳腺癌干细胞（BCSCs）在肿瘤复发和转移中起关键作用。乳腺癌细胞暴露于化疗会导致BCSCs富集。在此，我们发现化疗诱导谷胱甘肽S-转移酶ω1（GSTO1）的表达，这依赖于缺氧诱导因子1（HIF-1）和HIF-2。敲低GSTO1表达可消除卡铂诱导的BCSC富集，降低肿瘤起始和转移能力，并延迟化疗后肿瘤复发。GSTO1与兰尼碱受体RYR1相互作用并促进内质网钙释放。胞质钙水平升高激活PYK2→SRC→STAT3信号传导，导致多能性因子表达增加和BCSC富集。HIF抑制可阻断化疗诱导的GSTO1表达和BCSC富集。将HIF抑制剂与化疗联合使用可能改善乳腺癌的临床结局。
