Role of CD30 signaling in controlling the glucose metabolism in malignant lymphoma

• Grant number: 11/17410-1
• Support type: Regular Research Grants
• Duration: March 01, 2012 - February 28, 2014
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal researcher: Jörg Kobarg
• Grantee: Jörg Kobarg
• Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovações (Brasil). Campinas , SP, Brazil
• Assoc. researchers: Adriana Franco Paes Leme ; Ana Carolina de Mattos Zeri

Abstract

Normal cells generate high amounts of ATP by metabolizing glucose completely to carbon dioxide. In contrast, rapidly growing cancer cells restrict this metabolic pathway and profit from intermediate products for the biosynthesis of cell components and to influence the microenvironment. The lower molar ATP yield is compensated by increased glucose consumption. This metabolic switch is critically regulated by the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1). Its overexpression stimu-lates the glucose turnover and even immortalizes non-malignant cells. PGAM1 is generally controlled by the tumor suppressor p53 but functional p53 defects in many tumors allow PGAM1-dependent survival signaling. However, small molecule PGAM1 inhibitors are able to suppress cell growth, instead. Searching for p53-independent mechanisms to curb tumor cell glycolysis, we found that the receptor CD30 directly interacts with PGAM1. CD30 is selectively expressed on the malignant cells of anaplastic large cell lymphoma (ALCL) and agonistic stimulation of CD30 reduced glucose uptake and cell viability. In this project, we will test the hypothesis that the CD30-dependent loss of cell viability is due to a direct inhibition of the abnormal tumor cell glycolysis. Understanding this so far unknown signaling pathway and its impact on the glucose uptake and metabolome in tumor cells might provide new therapeutic options to damage cancer cells by limiting its deregulated glucose metabolism. (AU)