Ketamine inhibits aerobic glycolysis in colorectal cancer cells by blocking the NMDA receptor‐CaMK II‐c‐Myc pathway

Abstract

Aerobic glycolysis plays a crucial role in cancer progression. Ketamine is often used for cancer pain relief in clinical settings. Moreover, ketamine inhibits proliferation and induces apoptosis in many cancer cell types. However, the anti‐tumour mechanism of ketamine is still poorly understood. In the present study, we survey whether and how ketamine inhibits aerobic glycolysis in colon cancer cells. Glycolysis of colon cancer cells was determined by detecting the extracellular acidification rate in HT29 and SW480 cells. Quantitative real‐time PCR was employed to determine mRNA expression. Calcium levels were detected with a Fluo‐3 AM fluorescence kit. Micro‐positron emission tomography/computed tomography (microPET/CT) imaging was employed to assess glycolysis in the tumours of the xenograft model. Ketamine treatment inhibited colon cancer cell viability and migration in HT29 and SW480 cells. Moreover, ketamine decreased aerobic glycolysis and decreased the expression of glycolysis‐related proteins in HT29 and SW480 cells. MicroPET/CT demonstrated that ketamine decreased 18F‐FDG uptake in the xenograft model. In addition, ketamine inhibited c‐Myc expression and CaMK II phosphorylation and decreased calcium levels. Further, dizocilpine (an NMDAR inhibitor), and KN93 (a CaMK II inhibitor), decreased CaMK II phosphorylation, c‐Myc expression, and cancer cell glycolysis; these results were similar to those with ketamine treatment. Furthermore, the anti‐tumour effect of ketamine was counteracted by rapastinel (an NMDAR activator). Ketamine inhibited aerobic glycolysis in colon cancer cells probably by blocking the NMDA receptor‐CaMK II‐c‐Myc pathway, thus attenuating colon cancer cell viability and migration.

The downregulation of NCXs is positively correlated with the prognosis of stage II–IV colon cancer

“…In the pathological environment of intestinal malignant tumors, the original calcium homeostasis is broken, forming a “new homeostasis” in which the [Ca 2+ ]i of colorectal glandular epithelial tumors is increased, and the increase in [Ca 2+ ]i activates calmodulin kinase II (CaMKII) and hypoxia-inducible factor-1a (HIF1a), which are involved in tumor progression [ 26 , 27 ]. The upregulation of Ca 2+ /calmodulin-dependent protein kinase II and HIF1a in CC cells promoting tumor cell invasion and metastasis is related to aerobic glycolysis, and the activation of downstream factors MMPs and EMT also participates in tumor cell migration [ 53 , 54 ]. Some scholars have found that the mitochondrial Na + /Ca 2+ /Li + exchanger (NCLX) is significantly downregulated in patients with colorectal cancer.…”

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“…Western Blotting. Western blot analysis was performed as previously reported [30]. Briefly, 50 μg of total proteins in each lane was separated using 10% SDS-PAGE and transferred to nitrocellulose (NC) membranes.…”