Protein kinase A (PKA) is a holoenzyme, which composes of two regulatory subunits (R) and two catalytic subunits (C). The two C-subunits are maintained in an inactive conformation by an R-subunit dimmer51. Elevated intracellular cAMP binds to the R-subunit of PKA causing phosphorylation of C-subunit of PKA, and then the activated C-subunit of PKA phosphorylates a range of substrate proteins on serine/threonine residues to govern many biological processes in cells52. The broad-substrate specificity of PKA is directed toward specific intracellular substrates by a multigene family of A-kinase anchor proteins (AKAPs), which target PKA to distinct subcellular loci and coordinate multiple signaling enzymes in supramolecular complexes53. In the present study, IPA analysis revealed that VOSL or CD treatment inhibits the PKA signaling pathway. The flux of cAMP is governed by two sets of enzymes: adenyl cyclase (AC) and phosphodiesterase (PDE), the former is activated by G-proteins to synthesize cAMP from ATP, and the later terminates cAMP signaling by hydrolyzing it to AMP54. Moreover, accumulating documents demonstrated that in addition to anchoring PKA many AKAPs contribute to the local degradation of cAMP by co-localizing PDEs55. Therefore, we proposed that CD or VOSL can act as a G protein-coupled receptor (GPCR) inhibitor to inhibit G-protein activity and decrease cAMP synthesis, and the decreased levels of AC4 and intracellular cAMP in the CD- and VOSL-treated groups supported this deduction. Meanwhile, CD or VOSL treatment might up-regulate the phosphorylation level of AKAP8 with no obvious changes of the total AKAP8, and increase the local degradation of cAMP by co-localizing PDE4A5657. The decreased intracellular cAMP would cause inactivation of PKA and its downstream proteins, such as PDE, BAD, HSL, PHK, TH, NAFT, and Filamin, in turn affect the metabolic energy, lipolysis, glycolysis, tyrosine metabolism, and cytoskeletol regulation in cancer cells (Fig. 3C). These results are consistent with our previous report that is VOSL or CD treatment was able to attenuate the metabolic perturbation in energy metabolism, lipid metabolism, glycolysis, and tyrosine metabolism of MCF-7 xenograft mice3.