Abstract 3798: Cryptotanshinone inhibits lymphatic endothelial cell tube formation by suppressing VEGFR-3/ERK and small GTPase pathways

Abstract

Abstract Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here we show that CPT inhibited the tube formation of mouse lymphatic endothelial cells (LECs) in a concentration- and time-dependent manner. This effect was in part associated with inhibition of VEGFR-3 expression, as overexpression of VEGFR-3 conferred resistance to CPT inhibitory effect on tube formation in LECs, whereas downregulation of VEGFR-3 mimicked the effect of CPT, blocking the tube formation. Further study revealed that CPT inhibited phosphorylation of the extracellular signal-related kinase 1/2 (ERK1/2), a downstream effector of VEGFR-3. Overexpression of VEGFR-3 attenuated CPT inhibition of ERK1/2 phosphorylation, whereas downregulation of VEGFR-3 inhibited ERK1/2 phosphorylation in LECs. Ectopic expression of constitutively active MKK1 resulted in activation of ERK1/2, and partially prevented CPT inhibition of LEC tube formation. In addition, we also found that CPT inhibited protein expression and activities of Cdc42 and Rac1, but not RhoA. Downregulation of Cdc42 or Rac1 inhibited LEC tube formation, mimicking the effect of CPT. However, expression of constitutively active Cdc42 and Rac1 concurrently, but not Cdc42 or Rac1 alone, rendered resistance to CPT inhibition of LEC tube formation. The results suggest that CPT inhibits LEC tube formation at least in part through inhibiting VEGFR-3-mediated ERK and the small GTPase signaling pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3798. doi:1538-7445.AM2012-3798