Department of General Surgery, Pudong Branch of Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China.
Department of General Surgery and Pharmacology Laboratory of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China.
Int J Mol Med. 2018 Jul;42(1):579-588. doi: 10.3892/ijmm.2018.3638. Epub 2018 Apr 23.
Triple negative breast cancer (TNBC) has the lowest survival rate of the breast cancer subtypes owing to its aggressive and metastatic behavior. It has been reported that peritumoral adipose tissue contributes to the cell invasiveness and dissemination of TNBC. Emodin is an active anthraquinone derivative isolated from Rheum palmatum, with anticancer properties that have been reported to inhibit lung metastasis in a nude mouse xenograft model. In the present study, the effects of emodin on human TNBC cells and adipocytes were investigated in vivo and in vitro. The TNBC cell lines MDA‑MB‑231 and MDA‑MB‑453 were co‑cultured with human adipocytes and treated with either emodin or epirubicin. Cell proliferation was assessed by MTT assay and migration and invasion were examined using a wound healing assay and a Transwell assay. interleukin‑8, CC‑chemokine ligand 5 (CCL5) and insulin‑like growth factor‑1 levels in the culture supernatants were detected by ELISA. The epithelial‑mesenchymal transition (EMT) or metastasis associated markers were determined by western blot analysis. Nude mice fed with a high fat and sugar diet were used investigate the in vivo effect of emodin. The results showed that emodin inhibited TNBC proliferation and invasion more efficiently than epirubicin when co‑cultured with adipocytes by downregulating the level of CCL5 in adipocyte supernatants; inhibiting the expression level of protein kinase B (AKT); and activating glycogen synthase kinase‑3i (GSK3) and β‑catenin. This led to the suppressed expression of EMT‑ and invasion‑associated markers, including vimentin, snail, matrix metalloproteinase (MMP)‑2 and MMP‑9, and upregulation of E‑cadherin, contributing to the inhibition of invasion. The in vivo assay showed that emodin inhibited tumor growth, and suppressed the lung and liver metastasis of TNBC cells by decreasing the secretion of CCL5 in mice fed a high fat and sugar diet more efficiently when compared with epirubicin. In conclusion, emodin inhibited the secretion of CCL5 from adipocytes, inhibited the EMT of TNBC cells, and inhibited tumor growth and lung and liver metastasis, which indicated a novel role of emodin in preventing the metastasis of TNBC.
三阴性乳腺癌（TNBC）由于其侵袭性和转移性，其存活率是乳腺癌各亚型中最低的。有报道称，肿瘤周围脂肪组织有助于 TNBC 的细胞侵袭和扩散。大黄素是从大黄中分离得到的一种活性蒽醌衍生物，具有抗癌特性，据报道可抑制裸鼠异种移植模型中的肺转移。在本研究中，研究了大黄素对体内和体外人 TNBC 细胞和脂肪细胞的影响。将 TNBC 细胞系 MDA-MB-231 和 MDA-MB-453 与人类脂肪细胞共培养，并分别用大黄素或表柔比星处理。通过 MTT 测定法评估细胞增殖，通过划痕愈合试验和 Transwell 试验检测迁移和侵袭。通过 ELISA 检测培养上清液中白细胞介素-8（IL-8）、CC 趋化因子配体 5（CCL5）和胰岛素样生长因子-1（IGF-1）的水平。通过 Western blot 分析测定上皮-间充质转化（EMT）或转移相关标志物的表达。用高脂肪和高糖饮食喂养裸鼠来研究大黄素的体内作用。结果显示，当与脂肪细胞共培养时，大黄素通过下调脂肪细胞上清液中 CCL5 的水平，比表柔比星更有效地抑制 TNBC 的增殖和侵袭；抑制蛋白激酶 B（AKT）的表达水平；并激活糖原合酶激酶-3i（GSK3）和β-连环蛋白。这导致 EMT 和侵袭相关标志物的表达受到抑制，包括波形蛋白、蜗牛、基质金属蛋白酶（MMP）-2 和 MMP-9，同时 E-钙黏蛋白的表达上调，从而抑制了侵袭。体内试验表明，与表柔比星相比，大黄素在高脂肪和高糖饮食喂养的小鼠中更有效地抑制了 CCL5 的分泌，从而抑制了肿瘤生长，并抑制了 TNBC 细胞的肺和肝转移。总之，大黄素抑制脂肪细胞分泌 CCL5，抑制 TNBC 细胞的 EMT，抑制肿瘤生长和肺及肝转移，提示大黄素在预防 TNBC 转移方面具有新的作用。
