Glutamine Deprivation Induces Abortive S-Phase Rescued by Deoxyribonucleotides in K-Ras Transformed Fibroblasts

作者：Daniela Gaglio, Chiara Soldati, Marco Vanoni, Lilia Alberghina, Ferdinando Chiaradonna · 发表于：PLoS ONE · 年份：2009 · DOI：10.1371/journal.pone.0004715 · 被引用次数：171 · 研究领域：Cancer, Hypoxia, and Metabolism、Cancer Research and Treatments、Cancer Cells and Metastasis

BACKGROUND: Oncogene activation plays a role in metabolic reprogramming of cancer cells. We have previously shown that K-ras transformed fibroblasts have a stronger dependence on glycolysis and a reduced oxidative phosphorylation ability as compared to their normal counterparts. Another metabolic adaptation of cancer cells, that has long been established, is their propensity to exhibit increased glutamine consumption, although the effects induced by glutamine deprivation on cancer cells are still controversial. METHODOLOGY AND PRINCIPAL FINDINGS: Here, by using nutritional perturbations and molecular physiology, we show that reduction or complete depletion of glutamine availability in K-ras transformed fibroblasts causes a strong decrease of proliferation ability and a slower re-entry of synchronized cells into the cell cycle. The reduced proliferation is accompanied by sustained expression of cyclin D and E, abortive S phase entrance and is dependent on Ras signalling deregulation, since it is rescued by expression of a dominant negative guanine nucleotide exchange factor. The growth potential of transformed cells as well as the ability to execute the G(1) to S transition is restored by adding the four deoxyribonucleotides, indicating that the arrest of proliferation of K-ras transformed cells induced by glutamine depletion is largely due to a reduced supply of DNA in the presence of signalling pathways promoting G(1) to S transition. CONCLUSIONS AND SIGNIFICANCE: Our result...