Rai Rajani, Gong Essel Kathleen, Mangiaracina Benbrook Doris, Garland Justin, Daniel Zhao Yan, Chandra Vishal
Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Cancers (Basel). 2020 May 18;12(5):1273. doi: 10.3390/cancers12051273.
Sulforaphane exerts anti-cancer activity against multiple cancer types. Our objective was to evaluate utility of sulforaphane for endometrial cancer therapy. Sulforaphane reduced viability of endometrial cancer cell lines in association with the G/M cell cycle arrest and cell division cycle protein 2 (Cdc2) phosphorylation, and intrinsic apoptosis. Inhibition of anchorage-independent growth, invasion, and migration of the cell lines was associated with sulforaphane-induced alterations in epithelial-to-mesenchymal transition (EMT) markers of increased E-cadherin and decreased N-cadherin and vimentin expression. Proteomic analysis identified alterations in AKT, mTOR, and ERK kinases in the networks of sulforaphane effects in the Ishikawa endometrial cancer cell line. Western blots confirmed sulforaphane inhibition of AKT, mTOR, and induction of ERK with alterations in downstream signaling. AKT and mTOR inhibitors reduced endometrial cancer cell line viability and prevented further reduction by sulforaphane. Accumulation of nuclear phosphorylated ERK was associated with reduced sensitivity to the ERK inhibitor and its interference with sulforaphane activity. Sulforaphane induced apoptosis-associated growth inhibition of Ishikawa xenograft tumors to a greater extent than paclitaxel, with no evidence of toxicity. These results verify sulforaphane's potential as a non-toxic treatment candidate for endometrial cancer and identify AKT, mTOR, and ERK kinases in the mechanism of action with interference in the mechanism by nuclear phosphorylated ERK.
萝卜硫素对多种癌症类型具有抗癌活性。我们的目的是评估萝卜硫素在子宫内膜癌治疗中的效用。萝卜硫素降低了子宫内膜癌细胞系的活力，这与G/M期细胞周期阻滞、细胞分裂周期蛋白2（Cdc2）磷酸化以及内源性凋亡有关。萝卜硫素抑制细胞系的非锚定依赖性生长、侵袭和迁移，这与上皮-间质转化（EMT）标志物的改变有关，即E-钙黏蛋白增加，N-钙黏蛋白和波形蛋白表达减少。蛋白质组学分析确定了在石川子宫内膜癌细胞系中萝卜硫素作用网络中AKT、mTOR和ERK激酶的改变。蛋白质免疫印迹证实萝卜硫素抑制AKT、mTOR，并诱导ERK，同时下游信号发生改变。AKT和mTOR抑制剂降低了子宫内膜癌细胞系的活力，并阻止了萝卜硫素进一步降低其活力。核磷酸化ERK的积累与对ERK抑制剂的敏感性降低及其对萝卜硫素活性的干扰有关。萝卜硫素比紫杉醇更能诱导石川异种移植肿瘤的凋亡相关生长抑制，且没有毒性证据。这些结果证实了萝卜硫素作为子宫内膜癌无毒治疗候选药物的潜力，并确定了AKT、mTOR和ERK激酶在其作用机制中的作用，同时核磷酸化ERK对该机制存在干扰。
