Tubeimoside-1 Sensitizes TRAIL-induced Apoptosis via OTUD4-STAMBPL1-mediated c-FLIP downregulation

Abstract

Tubeimoside-1 (TBMS-1), the traditional Chinese medicinal herb, is commonly used as anti-cancer agent. Here, I investigated the effect of TBMS-1 in sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in cancer cells. Sub-lethal concentration of TBMS-1 alone and TRAIL alone did not affect cancer cell death, whereas combined treatment with TBMS-1 and TRAIL increase apoptotic cell death. Mechanistically, TBMS-1 destabilized c-FLIP expression through decrease of STAMBPL1, a deubiquitinating enzyme. STAMBPL1 interacted and deubiquitinased c-FLIP. Moreover, knockdown of STAMBPL1 markedly increased sensitivity to TRAIL, and overexpression of STAMBPL1 prevented TBMS-1 and TRAIL-induced apoptosis by regulating c-FLIP stabilization. Also, TBMS-1 downregulated OTUD4 mRNA expression. Decreased OTUD4 regulates STAMBPL1 expression and stability. These results provided that TBMS-1 increases TRAIL sensitization and induces apoptosis via OTUD4-STAMBPL1 mediated c-FLIP downregulation.

천연 약재로써 항암효과가 있는 Tubeimoside-1 (TBMS-1)와 TRAIL을 병합 처리하여 암세포에 대한 항암 효과를 조사하였다. 낮은 독성 농도의 TBMS-1와 TRAIL의 병합처리는 암세포에서 세포사멸을 증진시켰으나 정상세포에서는 효과가 없었다. TBMS-1은 탈유비퀴틴화 효소인 STAMBPL1의 감소를 통해 c-FLIP을 탈유비퀴틴화 시켜 c-FLIP 발현을 불안정화를 유도하였다. STAMBPL1의 발현억제는 TRAIL에 대한 민감성을 현저하게 증가시켰고, STAMBPL1의 과발현은 c-FLIP 안정화를 조절함으로써 TBMS-1 및 TRAIL-유도 세포 사멸을 억제하였다. TBMS-1은 OTUD4 mRNA 발현 감소를 유도하였다. TBMS-1에 의한 OTUD4 단백질의 발현 감소는 STAMBPL1의 단백질 발현 감소를 유도하였다. 이 결과는 TRAIL 매개의 세포 사멸 증진을 위한 민감제로 TBMS-1 가능성을 제시한다.