Hispidulin Enhances TRAIL-Mediated Apoptosis via CaMKK/AMPK/USP51 Axis-Mediated Bim Stabilization.

Seon Min Woo,Ju-Ock Nam,Shin Kim,Sang Hyun Kim,Kyoung-jin Min,Taeg Kyu Kwon,Seung Un Seo,Jong-Wook Park

doi:10.3390/cancers11121960

Seon Min Woo, Ju-Ock Nam + Show 6 more

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https://doi.org/10.3390/cancers11121960

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Abstract

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.

Highlights

Hispidulin (40,5,7-trihydroxy-6-methoxyflavone) is a natural compound [1,2], and has multiple functions, including anti-inflammation, anti-fungal, anti-epileptic, anti-hypnotic, and anti-osteoclastogenesis [3,4,5]
To uncover the novel effect of hispidulin in cancer cells, we investigated whether combination treatment with hispidulin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has synergistic effect
Combined treatment resulted in induction of sub-G1 population, and we detected cleaved PARP form in combined treated human renal carcinoma Caki cells (Figure 1A) and other human renal carcinoma (ACHN and A498), and human prostate DU145 cancer cells (Figure 1B)

Summary

Introduction

Hispidulin (40 ,5,7-trihydroxy-6-methoxyflavone) is a natural compound [1,2], and has multiple functions, including anti-inflammation, anti-fungal, anti-epileptic, anti-hypnotic, and anti-osteoclastogenesis [3,4,5]. Hispidulin induces apoptosis in leukemia and hepatoblastoma cells [6,7], and suppresses angiogenesis, leading to inhibition of tumor growth in xenograft mice models [8]. Anti-cancer effects of hispidulin are mediated by multiple signaling mechanisms, including inhibition of Akt, signal transducer and activator of transcription 3 (STAT3), and aurora kinase [7,9], and activation of AMP-activated protein kinase (AMPK) [10]. Hispidulin enhances sensitivity for anti-cancer drugs, such as temozolomide, sunitinib, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [10,11,12]. Sensitization of cancer cells to anti-cancer drug-induced apoptosis is related with down-regulation

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