Figure 6
(R,S′)-MNF blocks the growth of PANC-1 xenograft tumors in mice. (A) YAP/TAZ is regulated by the canonical Hippo pathway, AMPK-dependent phosphorylation, and the β-catenin destruction complex. YAP/TAZ translocation to the nucleus and interaction with TEAD transcription factors induces target genes such as GLI2, which encodes a transcription factor that controls the expression of several genes implicated in tumorigenesis (e.g., CYR61, MMP7, MCL1, BIRC2). Administration of (R,S′)-MNF led to significant downregulation in the expression of the indicated protein-encoded genes. Inhibition of the glycolytic pathway combined with reduced expression of LHDA, caused by the downregulation of c-Myc and HIF-1α gene and protein levels, negatively impacts the production of l-lactate by the tumor and its release into the circulation. Inhibition of glutamine uptake and its conversion to glutamate has a negative impact on the production of metabolic intermediates within the TCA cycle for mitochondrial ATP production. (B) Bitopic function of (R,S′)-MNF contributes to its anti-tumor activity. (R,S′)-MNF is a biased agonist of the β2-AR by promoting its coupling to the Gαs/adenylate cyclase (AC)/cAMP/PKA signal transduction, while preventing the recruitment and activation of β-arrestin 1, a critical regulator of tumorigenesis through ERK activation and formation of protein complexes with YAP and E2F transcription factors. The selective β2-AR antagonist, ICI 118551, inhibits salmeterol-stimulated cAMP production and associated PKA activity, while promoting basal β-arrestin 1 function. PKA blocks AKT- and ERK-mediated phosphorylation of target proteins and enhances LATS-dependent inhibition of YAP/TAZ pro-tumorigenic activity. LATS1/2 is activated by PKA, but inactivated by mechanical cues (e.g., integrin engagement) and GPCR-RhoA-mediated F-actin. Binding of the bioactive lipid, lysophosphatidylinositol (LPI), to GPR55 activates signaling cascades implicated in cell proliferation, invasion and survival through coupling to Gαq/11 and Gα12/13. Binding of (R,S′)-MNF to GPR55 directly inhibits its function. The illustrations were created using Canvas X Draw v.7.0.2 for macOS (Canvas GFX, Boston, MA).
