Metabolism in tumor cells, in which cell growth and survivability are significantly increased, differs from metabolism in non-tumorigenic cells. Although genetic mutations enable tumor cells to sidestep cell-cell contact inhibition to achieve cell proliferation orchestrated by growth factors, poor vascularization triggers chronic nutrient deficiency and declined concentrations of oxygen in the tumor microenvironment (TME). In order to adapt to these cruel environmental stresses and survive, tumor cells change their metabolic pathways to capture exterior metabolites and boost the activities of metabolic enzymes. It is described as Warburg Effect that tumor cells adjust their metabolism to become more oncogenic to meet the needs of elevated proliferation and eventually contribute to metastasis and invade other tissues.
Aberrant cancer metabolism, including aerobic glycolysis and increased oncometabolite production, plays essential roles in the genesis and invasion of tumors, as well as resistance to drugs. There is an array of well-known oncogenic signaling pathways, including PI3K/AKT pathway, MYC pathway, and Hippo pathway, modulating the expression of genes involved in metabolism and enhancing the activities of metabolic enzymes.
Fig.1 Cancer metabolism promotes redox homeostasis during metastasis.1
Previous studies have confirmed that there are strong correlations between oncogenic signaling pathways and phenotypes of abnormal metabolism, making cancer metabolism a potential target for therapeutic interventions. Some metabolic phenotypes of tumor cells have been recognized as biomarkers for diagnosis, while abnormal cancer progression and resistance to treatment mediated by cancer metabolism jointly underscore the urgent need for metabolism-targeting antitumor therapies.
In addition to targeting regulators in oncogenic signaling pathways involved in cancer metabolism, which have been well-investigated and applied in immunotherapies as tumor suppressors and oncoproteins, other molecules and reactions participating in metabolism can also be considered as targets, including metabolic enzymes and oxidative phosphorylation (OXPHOS).
Metabolic enzymes functioning in the metabolic pathways of glucose, glutamine, and fatty acid have been regarded as promising targets for drug development. Significant overexpression levels of glycolytic enzymes are observed in tumor cells and their activities are enhanced to improve aerobic glycolysis. Multiple inhibitors targeting these enzymes have been designed and tested in experiments and trials. For instance, MCT-1 is a transporter for the secretion to the TME of lactate, the final product of aerobic glycolysis. An anti-MCT-1 inhibitor is demonstrated to block lactate-mediated tumor progression, exhibiting encouraging anticancer effects, when applied in combination with other drugs.
It is reported that several types of cancers depend on OXPHOS for bioenergetics, which makes mitochondrial OXPHOS inhibition a candidate target for therapeutic strategies of cancers. Various inhibitors targeting OXPHOS have been developed and studied, demonstrating antitumor effects in many cancers. For example, in some studies, it is observed that energy stress mediated by OXPHOS inhibition stimulates the activation of AMPK. Since AMPK is a negative regulator of cellular anabolic metabolism, modulating multiple processes including fatty acid synthesis, GLUT1 expression, and the mevalonate pathway, it is indicated that OXPHOS inhibitors can concurrently suppress multiple metabolic pathways.
As a pioneer in antibody research and development, Amerigo Scientific has gained rich knowledge and resources in targeting cancer metabolism. We are proud to introduce our antibody products targeting signaling pathways, metabolic enzymes, and other potential targets in cancer metabolism for various applications to our esteemed clients around the world, please feel free to for more information.
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