RRM1-induced metastasis suppression through PTEN-regulated pathways

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Abstract
Lung cancer is the leading cause of cancer-related mortality in the United States. Only 15% of patients with this disease survive 5 years or longer. Early metastatic spread is the single most important reason for this poor outcome. The survival of patients with pathological stage I disease, that is, no evidence for metastatic spread, and molecular aberrations on chromosome 11p15.5 is equal to that of patients with stage II disease, that is, metastatic spread to hilar lymph nodes. RRM1 is a gene in this region, and it is haploinsufficient in at least 34% stage I patients. Here, we show that overexpression of RRM1 in human and mouse lung cancer cell lines induced PTEN expression, reduced phosphorylation of focal adhesion kinase (FAK), suppressed migration, invasion, and metastasis formation, and increased survival in an animal model. Increased PTEN expression was required for the RRM1-induced suppression of cell motility and FAK phosphorylation. We conclude that RRM1 functions as a metastasis suppressor gene through induction of PTEN expression.