14-3-3 σ Expression Effects G2/M Response to Oxygen and Correlates with Ovarian Cancer Metastasis

Background: In vitro cell culture experiments with primary cells have reported that cell proliferation is retarded in the presence of ambient compared to physiological O-2 levels. Cancer is primarily a disease of aberrant cell proliferation, therefore, studying cancer cells grown under ambient O-2 may be undesirable. To understand better the impact of O-2 on the propagation of cancer cells in vitro, we compared the growth potential of a panel of ovarian cancer cell lines under ambient (21%) or physiological (3%) O-2. Principal Findings: Our observations demonstrate that similar to primary cells, many cancer cells maintain an inherent sensitivity to O-2, but some display insensitivity to changes in O-2 concentration. Further analysis revealed an association between defective G2/M cell cycle transition regulation and O-2 insensitivity resultant from overexpression of 14-3-3 sigma. Targeting 14-3-3 sigma overexpression with RNAi restored O-2 sensitivity in these cell lines. Additionally, we found that metastatic ovarian tumors frequently overexpress 14-3-3 sigma, which in conjunction with phosphorylated RB, results in poor prognosis. Conclusions: Cancer cells show differential proliferative sensitivity to changes in O-2 concentration. Although a direct link between O-2 insensitivity and metastasis was not determined, this investigation showed that an O-2 insensitive phenotype in cancer cells to correlate with metastatic tumor progression.