Effects of BPTES and PFK15 Combination on MCF7 and MDAMB231 Cell Lines

Project no. 23444 · Status: Kapanmış (Yayın bekleniyor) · 2022

Summary

Solid tumors are characterized by uncontrolled cell proliferation and growth, representing a highly complex and heterogeneous group of diseases. These types of cancers differ metabolically from healthy cells; the changes in the metabolism of cancer cells contribute to cellular proliferation and macromolecular biosynthesis. Cancer cells require many different components to survive and grow, but the two fundamental nutrients are glucose and glutamine. In particular, the metabolism of cancer cells is characterized by high levels of glutamine consumption.In the context of cancer treatment, research targeting glutamine metabolism has focused on the enzyme Glutaminase 1 (GLS1); this enzyme has been studied in many types of cancer. However, the role of another glutaminase isoform, Glutaminase 2 (GLS2), in cancer cells is still not clearly understood. The BPTES compound, used in glutaminase inhibition, has demonstrated superior performance in various cancer types compared to other inhibitors.The glycolysis process is also a significant metabolic pathway in cancer cells. One of the central regulators of glycolysis, the enzyme 6-phosphofructo-2-kinase: fructose-2,6-bisphosphatase (PFKFB), catalyzes the synthesis and breakdown of fructose-2,6-bisphosphate. It has four different isoforms, and particularly PFKFB3 is highly expressed in many human tumors and is notable for its high kinase activity. The inhibition of PFKFB3's kinase activity with small molecule inhibitors is considered a promising approach for cancer treatments. In particular, the inhibitor named PFK15 has attracted attention for its antitumor effects in various cancer types and is emerging as a potential target in cancer therapy.In this study, the inhibition of glycolysis and glutaminolysis mechanisms in MCF-7 and MDA-MB-231 cell lines was targeted, and the anticancer properties in these cell lines were investigated. Additionally, the effects of suppressing these two pathways on the expression levels of the PFKFB3 and GATA3 genes were examined. The synergistic and cytotoxic effects of the BPTES and PFK15 combination on the MCF-7 Luminal A breast cancer cell line have been documented through cytotoxicity and combination analyses. Furthermore, the apoptotic effects of this combination have been supported by an apoptosis study. The BPTES and PFK15 combination is a suitable candidate for advanced studies on model organisms used in Luminal A type breast cancer research.On the other hand, the MDA-MB-231 triple-negative breast cancer cell line is generally difficult to treat. However, studies have shown that combination applications at high concentrations have more cytotoxic and apoptotic effects in this cell line. These findings encourage more detailed studies on model organisms.The expression of glutaminase and glutaminolysis is notably more prominent in aggressive types of breast cancer. In triple-negative breast cancer, the expression of glutaminolysis is significantly higher. In the Luminal A breast cancer cell line, the noteworthy expression of the GATA3 transcription factor associated with GLS2 expression may be related to the ErbB2/ErbB4/p38γ/GATA3/miR-200b/Suz12 signaling pathways. The activation of these pathways can lead to significant changes in cell behaviors, playing critical roles in cancer progression. In this context, further research on the expression dynamics of GATA3 and GLS2 could contribute to the identification of new therapeutic targets for breast cancer treatment.The results of this study demonstrate that the inhibition of glycolysis and glutaminolysis plays a critical role in the MDA-MB-231 cell line and that this inhibition has significant effects on cell death. Additionally, the inhibition of the glycolysis and glutaminolysis pathways, especially in combination, leads to a significant decrease in cell viability and triggers apoptotic processes. However, a clear correlation between these effects and gene expression levels has not been established. Therefore, further studies are needed to better understand the molecular mechanisms of glycolysis and glutaminolysis inhibition. These studies could facilitate a better understanding of glycolysis and glutaminolysis pathways as potential therapeutic targets in cancer treatment.

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