XIAOPI formula promotes breast cancer chemosensitivity via inhibiting CXCL1/HMGB1-mediated autophagy
XIAOPI formula promotes breast cancer chemosensitivity via inhibiting CXCL1/HMGB1-mediated autophagy
复制标题
消痞方通过抑制CXCL1/HMGB1介导的自噬提高乳腺癌化疗敏感性
DOI：
10.1016/j.biopha.2019.109519
复制
发表时间：
2019-12-01
影响因子：
7.5
通讯作者：
Wang, Zhiyu
中科院分区：
文献类型：
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作者：
Wang, Neng;Yang, Bowen;Wang, Zhiyu
消癖方是一种国家批准的药物，用于高乳腺癌风险患者。本课题组前期研究证实消痞方通过抑制CXCL 1表达抑制乳腺癌转移，并推测“自噬”可能是其最核心的抗癌机制之一。然而，消痞方能否与化疗药物合用，其协同作用机制尚不清楚。在本研究中，消痞方在非细胞毒性剂量下可协同增强乳腺癌细胞MDA-MB-231和MCF-7的化疗敏感性。我们发现雷帕霉素诱导的自噬可降低乳腺癌细胞对消痞方的化疗敏感性，且消痞方的自噬抑制和化疗增敏活性具有CXCL 1依赖性。证据来自于消痞方与单独雷帕霉素或紫杉醇联合使用时CXCL 1表达降低。此外，消痞方对CXCL 1过表达的LC 3-II和ABCG 2信号的抑制作用减弱，而对P62的上调作用则再次减弱。高通量qPCR（HT-qPCR）分析鉴定HMGB 1为消痞方在化学增敏乳腺癌中的主要自噬靶标。进一步验证表明消痞方主要通过CXCL 1/HMGB 1自噬轴发挥化疗敏感性。最后，我们建立了携带MDA-MB-231乳腺癌细胞的小鼠和斑马鱼异种移植模型，发现消痞方安全地增强了乳腺癌对紫杉醇的体内化疗敏感性。综上所述，消痞方通过抑制CXCL 1/HMGB 1介导的自噬作用，是一种潜在的乳腺癌辅助治疗药物，且安全性好。
XIAOPI formula is a national approved drug prescribed to patients with high breast cancer risk. Previously we demonstrated that XIAOPI formula could inhibit breast cancer metastasis via suppressing CXCL1 expression, and postulated that "autophagy in cancer" might be one of its most core anti-cancer mechanisms. However, whether XIAOPI formula could be simultaneously applied with chemodrugs and their synergistic mechanisms are still remained unknown. In the present study, XIAOPI formula at non-cytotoxic doses could synergistically enhance the chemosensitivity of breast cancer cells MDA-MB-231 and MCF-7. We found that rapamycin-induced autophagy could reduce the chemosensitivity of breast cancer cells to XIAOPI formula, and the autophagy suppression and chemosensitizing activity of this formula was CXCL1-dependent. The evidence came from that XIAOPI formula was associated with a lower expression of CXCL1 combined with either rapamycin or taxol alone. Besides, the inhibitory effect of XIAOPI formula on the LC3-II and ABCG2 signals was weakened following CXCL1 over-expression, whereas P62 upregulation induced by XIAOPI formula was re-declined. A high throughput qPCR (HT-qPCR) assay identified HMGB1 as the main autophagic target of XIAOPI formula in chemosensitizing breast cancer. and furhter validation suggested XIAOPI formula exerted chemosensitivity mainly via CXCL1/HMGB1 autophagic axis. Finally, we generated both mice and zebrafish xenotransplantation models bearing MDA-MB-231 breast cancer cells, and found that XIAOPI formula safely enhanced in vivo taxol chemosensitivity on breast cancer. Taken together, XIAOPI formula is a potential adjuvant drug via inhibiting CXCL1/HMGB1-mediated autophagy for breast cancer treatment with good safety.