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 σ. Targeting 14-3-3 σ overexpression with RNAi restored O(2) sensitivity in these cell lines. Additionally, we found that metastatic ovarian tumors frequently overexpress 14-3-3 σ, 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.