The Bioactivity and Modulatory Properties of Functionalized Bacterial Glutaminase in Cancer Biology

Abstract

Background:Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide. The metabolic dependency of breast cancer cells on glutamine, a phenomenon known as "glutamine addiction," provides a potential therapeutic target. Glutaminase, an enzyme responsible for converting glutamine to glutamate, plays a crucial role in this metabolic pathway.Objective:This study aims to explore the therapeutic potential of functionalized bacterial glutaminase in breast cancer treatment. By conjugating the enzyme with breast cancer-specific targeting ligands, we hypothesize that the selective disruption of glutamine metabolism in cancer cells can be achieved, thereby inhibiting cell proliferation and survival.Methods:Functionalized bacterial glutaminase was synthesized by conjugating bacterial glutaminase with breast cancer-specific ligands. MCF-7 and MDA-MB-231 breast cancer cell lines were treated with varying concentrations of the functionalized enzyme. Cell viability was assessed using the MTT assay. Metabolic effects were evaluated by measuring glutamine uptake, glutamate production, and the activities of key metabolic enzymes glutaminase 1 (GLS1), glutamate dehydrogenase (GDH). mTOR(mammalian target of rapamycin ) phosphorylation, a marker of cell growth signaling, was also analyzed.Results:Functionalized bacterial glutaminase exhibited dose-dependent and time-dependent cytotoxicity in both MCF-7 and MDA-MB-231 cells. Treatment significantly reduced GLS1 and GDH activities, as well as mTOR phosphorylation levels, indicating effective disruption of cancer cell metabolism and signaling pathways. Notably, MDA-MB-231 cells showed higher sensitivity to the treatment.Conclusion:Functionalized bacterial glutaminase demonstrates significant anti-cancer activity against breast cancer cells by selectively targeting glutamine metabolism. Its dual impact on metabolic and signaling pathways suggests a promising therapeutic strategy for breast cancer. Further in vivo studies and the exploration of combination therapies are warranted to realize its clinical potential fully.