Page 150 - D. Cancer biology

[D. Cancer biology-97]

Effect of hispidulin on TRAIL-induced apoptosis in cancer

cells through CaMMKβ/AMPK/USP51 axis-mediated bim

stabilization

Seon Min Woo¹, Kyoung-jin Min¹, Taeg Kyu Kwon¹

¹Immunology, Keimyung University, Daegu 42601, Korea

Hispidulin, a natural compound present in herbs, has anti-cancer effects. Here, we investigated whether hispidulin
sensitizes human carcinoma cells to apoptosis induced by TRAIL. Sub-lethal dosages of TRAIL alone and hispidulin
alone does not increase apoptosis, but hispidulin increases sensitivity to TRAIL, resulting in induction of apoptosis

in hispidulin plus TRAIL-treated cancer cells. In addition, combined treatment with hispidulin and TRAIL also reduced
tumor growth and increased apoptosis in xenograft models. However, hispidulin did not alter cell viability in human

renal normal mesangial cells and human skin fibroblast. Hispidulin markedly increased the BH3-only proteins Bim
at the post-translational levels. Depletion of Bim with siRNA significantly blocked hispidulin plus TRAIL-induced

apoptosis. Furthermore, we found that activation of AMPK by hispidulin has a crucial role in Bim proteins stability
through up-regulation of USP51 expression. Our findings suggest that USP51-dependent stabilization of Bim by

AMPK activation plays a critical role in hispidulin-mediated sensitization of cancer cells to apoptosis induced by
TRAIL.