A study of how cancer cells get energy and raw materials for growth from glucose opens doors to new therapies
Ludwig researchers have elucidated a key mechanism by which cancer cells change how they metabolize glucose to generate the energy and raw materials required to sustain runaway growth.
Published online in Cell Metabolism, the Ludwig Cancer Research study also reveals how the aggressive brain cancer glioblastoma harnesses the mechanism to resist targeted therapies that should disrupt this capability-known as the Warburg effect-and suggests how such resistance might be overcome. In detailing the molecular circuitry of the phenomenon, the researchers uncover several possible targets for new drugs that might disrupt cancer cell metabolism to destroy tumors.
"Cancer and other fast-growing cells extract energy from glucose using a process that ordinarily kicks in only when oxygen is in short supply," explains Ludwig scientist Paul Mischel, MD, who is based at the University of California, San Diego School of Medicine. "This allows them to thread the needle: they get the energy they need from glucose but also retain the carbon-based building blocks for molecules like lipids, proteins and DNA, which dividing cells need in large quantities."
Until recently, relatively little was known about the biochemical circuits that induce this vital metabolic shift in cancer cells. Earlier this year, however, Mischel and his colleagues published a study describing how an aberrant growth signal found in many glioblastomas is channeled to induce the Warburg effect. That signaling cascade, which involves the key proteins PI3 kinase (PI3K), Akt and mTORC1, culminates in the activation of a transcription factor-a controller of gene expression-named c-Myc. "In many cancer cells," says Mischel, "c-Myc seems to be a lever that links growth signaling pathways with the machinery that controls the uptake and use of nutrients."
In the current study, Mischel, who did the research in collaboration with Ludwig researchers Kenta Masui, MD, PhD and Web Cavenee, PhD, both also at UC San Diego, identifies a second interacting biochemical cascade that is independent of the PI3K-Akt-mTORC1 signal and uses distinct biochemical circuits and an unusual mechanism to turn on c-Myc. This pathway, Mischel and his colleagues report, depends on signals from a protein complex named mTORC2. The researchers show that when mTORC2 is switched on, it silences two other transcription factors, FoxO1 and FoxO3, which would otherwise suppress the activation of c-Myc in the nucleus of the cell. Further, they learned that the silencing of the FoxOs occurs through a chemical modification-known as acetylation-a process that has not been well understood.