Cancer Cells Exploit Alternative Pathways When Mutations Block the Krebs Cycle

Since mutations in the genome of cancer cells often force tumors to use metabolic pathways not found in normal cells, cancer researchers believe that drugs targeting these pathways will be able to destroy tumors with fewer adverse side effects.

Some tumors harbor mutations in the citric acid cycle (CAC or Krebs cycle) or electron transport chain (ETC) that disable normal oxidative mitochondrial function. However, how cells from such tumors generate precursors for macromolecular synthesis has been unclear.

In a paper, investigators at the University of Texas Southwestern Medical Center (Dallas, USA) showed that tumor cells with defective mitochondria used glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation.

They reported in the November 20, 2011, online edition of the journal Nature that this pathway used mitochondrial and cytosolic isoforms of NADP+/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate to provide both the acetyl-coenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors.

“There is no pathway that has been more extensively studied over the years than the Krebs cycle,” said senior author Dr. Ralph J. DeBerardinis, assistant professor of pediatrics and genetics at the University of Texas Southwestern Medical Center. “The fact that with relatively modest manipulation, it can run in reverse is incredibly fascinating. If we hone in on this reverse pathway, then we may be able to prevent the growth of certain types of cancer. It has long been thought that targeting tumor-specific metabolic pathways would lead to an effective way to treat cancer. This is one of the few metabolic pathways that may actually exist specifically in tumors.”

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University of Texas Southwestern Medical Center