Figure 6.

Inhibition of inflammation-induced EMT by PTs. Lupane-, oleanane-, and ursane-type PTs exhibit a variety of EMT inhibition mechanisms. PTs inhibit TGF-β signaling pathways (UA, AA, celastrol, pristimerin, C DDO-Me) and the downstream SMAD (UA, AA, celastrol, β-peltoboykinolic acid, glycyrrhizin) and ERK (UA, UNA, OA) signaling axes. PT-induced disruption of integrin signaling involves integrin αVβ5 expression inhibition (UA) and activation of FAK and AKT (BA, SYK023). The blockade of F-actin polymerization by the lupane-type PTs BA and SYK023 is mediated by the downregulation of Synpo, which presumably activates Smurf1-dependent ubiquitination of RhoA. In contrast, BA disrupts the Skp2-SCF E3 ligase complex, thereby protecting E-cadherin from degradation. The ursane-type PTs UA and AA inhibit β-catenin through a GSK-β-dependent mechanism. The effect of UA on EMT is also associated with repression of the AEG-1 oncogene, which regulates several steps in the NF-κB signaling pathway, and inhibition of the EGFR signaling pathway. Glycyrrhizin inhibits EMT induced by HMGB1, a nuclear protein released from tumor cells (TLR4 and RAGE are shown as possible HMGB1 receptors due to uncertainty in the downstream pathway). Some triterpenoids have an unknown mechanism of action but regulate EMT-associated genes (SM, evoditrilone A, pristimerin). Downward (↓) and upward (↑) arrows indicate downregulation and upregulation of expression, respectively.