7-amino carboxycoumarin 2 inhibits lactate induced epithelial-to-mesenchymal transition via MPC1 in oral and breast cancer cells.

Autor: Umar SM; Department of Medical Oncology (Lab), All India Institute of Medical Sciences, New Delhi, India., Dev AJR; Department of Medical Oncology (Lab), All India Institute of Medical Sciences, New Delhi, India., Kashyap A; Department of Medical Oncology (Lab), All India Institute of Medical Sciences, New Delhi, India., Rathee M; Department of Medical Oncology (Lab), All India Institute of Medical Sciences, New Delhi, India., Chauhan SS; Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India., Sharma A; Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India., Prasad CP; Department of Medical Oncology (Lab), All India Institute of Medical Sciences, New Delhi, India.
Jazyk: angličtina
Zdroj: Cell biology international [Cell Biol Int] 2024 Aug; Vol. 48 (8), pp. 1185-1197. Date of Electronic Publication: 2024 May 21.
DOI: 10.1002/cbin.12172
Abstrakt: Lactate is an oncometabolite that play important role in tumor aggressiveness. Lactate from the tumor microenvironment (TME) is taken up by cancer cells as an energy resource via mitochondrial oxidative phosphorylation (or OXPHOS). In the present study, by using an online meta-analysis tool we demonstrated that in oral squamous cancer cells (OSCCs) glycolytic and OXPHOS governing genes are overexpressed, like in breast cancer. For experimental demonstration, we treated the OSCC cell line (SCC4) and breast cancer cells (MDA-MB-231) with sodium L-lactate and analyzed its effects on changes in EMT and migration. For the therapeutic intervention of lactate metabolism, we used AZD3965 (an MCT1 inhibitor), and 7ACC2 (an MPC inhibitor). Like breast cancer, oral cancer tissues showed increased transcripts of 12 genes that were previously shown to be associated with glycolysis and OXPHOS. We experimentally demonstrated that L-lactate treatment induced mesenchymal markers and migration of cancer cells, which was significantly neutralized by MPC inhibitor that is, 7ACC2. Such an effect on EMT status was not observed with AZD3965. Furthermore, we showed that lactate treatment increases the MPC1 expression in both cancer cells, and this might be the reason why cancer cells in the high lactate environment are more sensitive to 7ACC2. Overall, our present findings demonstrate that extracellular lactate positively regulates the MPC1 protein expression in cancer cells, thereby putting forward the notion of using 7ACC2 as a potential therapeutic alternative to inhibit malignant oxidative cancers. Future preclinical studies are warranted to validate the present findings.
(© 2024 International Federation of Cell Biology.)
Databáze: MEDLINE
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