Zhang Xiaomin, Zhang Yanmei, Du Wei
Department of Anesthesiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, N0. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning Province, China.
BMC Cancer. 2024 Dec 18;24(1):1535. doi: 10.1186/s12885-024-13290-7.
The analgesic effect of ketamine in cancer pain remains controversial. This research investigates the role of ketamine in bone metastasis-induced cancer pain in breast cancer (BC) and its associated molecular network.
BC cell lines MDA-MB-231 and ZR-75-1 were treated with ketamine and malignant behaviors were assessed through CCK-8, colony formation, and Transwell assays. To evaluate the pro-osteoclastic effect in vitro, BC cells were co-cultured with RAW 264.7 cells. Alterations in the expression of SRC proto-oncogene (SRC), early growth response 1 (EGR1), and cystatin E/M (CST6) were induced in BC cells using lentivirus. MDA-MB-231 cells were injected intracardially into nude mice to examine tumor bone metastasis in vivo. Molecular interactions between SRC and EGR1, as well as between EGR1 and CST6 were analyzed via immunoprecipitation and luciferase assays.
Ketamine treatment suppressed viability, proliferation, migration and invasiveness, epithelial-mesenchymal transition, and pro-osteoclastic effect in BC cells. Ketamine also reduced osteoclastogenesis and tumor bone metastasis burden and alleviated pain in nude mice. SRC was identified as a target of ketamine. Overexpression of SRC in BC cells blocked the effects of ketamine. SRC bound to the EGR1 promoter, suppressing EGR1 transcription, whereas EGR1 activated CST6 transcription. Either EGR1 or CST6 overexpression counteracted the function of SRC overexpression and decreased the viability of BC cells and their pro-osteoclastic effect in vitro and in vivo.
This study demonstrates that ketamine alleviates BC cell-induced osteoclastogenesis and tumor bone metastasis by suppressing SRC and restoring the EGR1/CST6 axis.
氯胺酮在癌痛中的镇痛作用仍存在争议。本研究探讨氯胺酮在乳腺癌（BC）骨转移诱导的癌痛中的作用及其相关分子网络。
用氯胺酮处理BC细胞系MDA-MB-231和ZR-75-1，并通过CCK-8、集落形成和Transwell实验评估其恶性行为。为了评估体外促破骨细胞作用，将BC细胞与RAW 264.7细胞共培养。使用慢病毒诱导BC细胞中SRC原癌基因（SRC）、早期生长反应1（EGR1）和胱抑素E/M（CST6）表达的改变。将MDA-MB-231细胞心内注射到裸鼠体内，以检测体内肿瘤骨转移情况。通过免疫沉淀和荧光素酶实验分析SRC与EGR1之间以及EGR1与CST6之间的分子相互作用。
氯胺酮处理抑制了BC细胞的活力、增殖、迁移和侵袭能力、上皮-间质转化以及促破骨细胞作用。氯胺酮还减少了破骨细胞生成和肿瘤骨转移负担，并减轻了裸鼠的疼痛。SRC被确定为氯胺酮的靶点。BC细胞中SRC的过表达阻断了氯胺酮的作用。SRC与EGR1启动子结合，抑制EGR1转录，而EGR1激活CST6转录。EGR1或CST6的过表达抵消了SRC过表达的功能，并降低了BC细胞的活力及其在体外和体内的促破骨细胞作用。
本研究表明，氯胺酮通过抑制SRC并恢复EGR1/CST6轴来减轻BC细胞诱导的破骨细胞生成和肿瘤骨转移。
