Abstract
Honokiol is a natural biphenolic compound extracted from traditional Chinese medicine Magnolia species, which have been known to display various biological effects including anti-cancer, anti-proliferative, anti-angiogenic, and anti-metastatic activities in cancer cells. Here, we found that honokiol sensitizes cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through downregulation of anti-apoptotic proteins survivin and c-FLIP. Ectopic expression of survivin and c-FLIP markedly abolished honokiol and TRAIL-induced apoptosis. Mechanistically, honokiol induced protein degradation of c-FLIP and survivin through STAMBPL1, a deubiquitinase. STAMBPL1 interacted with survivin and c-FLIP, resulted in reduction of ubiquitination. Knockdown of STAMBPL1 reduced survivin and c-FLIP protein levels, while overexpression of STAMBPL1 inhibited honokinol-induced survivin and c-FLIP degradation. Our findings provided that honokiol could overcome TRAIL resistance through survivin and c-FLIP degradation induced by inhibition of STAMBPL1 expression.
Highlights
Even though tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is characterized by induction of death receptor (DR)-mediated apoptosis in cancer cells, most of cancer cells show resistance to TRAIL [1,2]
We found that the nuclear chromatin condensation and DNA fragmentation were markedly increased in combined treatment with honokiol and TRAIL (Supplementary Figure S1B and Figure 1D)
Overexpression of survivin or c-FLIP markedly prevented sub-G1 population and PARP cleavage by honokiol plus TRAIL treatment (Figure 3A,B), while overexpression of Mcl-1 still induced apoptosis by combined treatment (Figure 3C). These results suggest that decrease of survivin and c-FLIP by honokiol contributes to induction of TRAIL sensitivity
Summary
Even though tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is characterized by induction of death receptor (DR)-mediated apoptosis in cancer cells, most of cancer cells show resistance to TRAIL [1,2]. The typical factors of TRAIL resistance are downregulation of DRs (DR4 and DR5) and upregulation of decoy receptors (DcR1 and DcR2) [3,4]. Overexpression of anti-apoptotic proteins, such as Bcl-2 family, IAP family, and c-FLIP, or downregulation of pro-apoptotic. Bcl-2 family proteins decrease TRAIL-induced cancer cell death [5]. Previous studies investigated that honokiol increases mitochondrial dysfunction, resulting in induction of ROS-dependent apoptosis in cancer cells [11,12]. Honokiol is regarded as sensitizer to increase anti-cancer effects of chemotherapeutic agents in various cancer cells.
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