Alleviating role of ketamine in breast cancer cell-induced osteoclastogenesis and tumor bone metastasis-induced bone cancer pain through an SRC/EGR1/CST6 axis.

Ketamine suppresses breast cancer cell growth, spread, and the ability of those cells to promote bone-destroying osteoclast activity. In cell lines and a mouse model of bone metastasis, ketamine reduced tumor burden and pain. The drug works by inhibiting the SRC protein, which in turn restores the EGR1/CST6 signaling pathway. Overexpression of SRC blocked ketamine's effects, while restoring EGR1 or CST6 counteracted SRC's harmful actions. The findings indicate that ketamine alleviates bone metastasis and associated pain in breast cancer through this molecular mechanism.

Study at a glance

Abstract

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.