Cellular cAMP Content and Mitochondrial Profile Define Different Subtypes of Ovarian Cancer Cells

Ovarian cancer (OC) is an aggressive and lethal gynecologic cancer due to its asymptomatic nature resulting in a late diagnosis. OC encompasses distinct histological subtypes, with serous OC representing the most common and aggressive form. However, within the same histological OC subtype, additional heterogeneity has been found in terms of genetic mutations and metabolic profiles probably contributing to treatment response. In cancer, metabolic reprogramming strongly involves mitochondria. Mitochondrial function can be regulated by the cAMP pathway, and its deregulation has been reported in various cancers including OC. Here we analyzed two serous OC cell lines, OC316 and OV56, and eleven human OC tissues. OC316 cell lines showed elevated cAMP level with respect to OV56. The high cAMP levels were associated with activation of thecAMP/PKA/CREB/PGC-1α axis resulting in increased mitochondrial biogenesis, respiratory chain activity, modulation of mitochondrial dynamics and apoptosis resistance. Accordingly, principal component analysis (PCA) of the twenty-three biochemical parameters, in eleven human OC tissues, classified OC into two groups showing different cAMP levels associated with distinct mitochondrial profiles. This analysis highlights a cAMP-dependent stratification revealing two mitochondrial subpopulations within serous OC. These findings indicate that the molecular heterogeneity of OC poses a challenge for understanding disease mechanisms and developing effective targeted therapies.