Figure 6

Modeling the potential cellular roles of three genes upregulated by AnAc in MCF-7 and MDA-MB-231 cells. As indicted in Fig. 1, MetaCore analysis identified only one pathway for these three common upregulated genes: Transcription Sirtuin6 (SIRT6) regulation and function. AnAc increased GPR176 in both cell lines. GPR176 is a GZ-coupled receptor that decreases cAMP, which would be expected to decrease PKA, both of which would maintain SIRT6 protein by preventing its ubiquitinylation and proteasome-mediated degradation (dashed arrow,+). AnAc increased ZPTB20, a transcriptional repressor that inhibits FOXO1 transcription. SIRT6 deacetylates FOXO1 which decreases its nuclear localization, hence reducing glycolysis, pentose phosphate pathway, lipid metabolism, and cancer stem cell biogenesis. AnAc increased PDK4 in both MCF-7 and MDA-MB-231 cells. PDK4 phosphorylates and inhibits pyruvate dehydrogenase (PDH), which would be expected to decrease acetyl CoA, possibly inhibiting the TCA cycle, oxidative phosphorylation, and FA biosynthesis. Taken together, the observed gene changes are commensurate with the observed ability of AnAc to inhibit the proliferation of these two breast cancer cell lines.