Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5)

Abstract

Curcumin exhibits anti-inflammatory and antitumor activities. Although its functional mechanism has not been elucidated so far, numerous studies have shown that curcumin induces apoptosis in cancer cells. In the present study, we show that subtoxic concentrations of curcumin sensitize human renal cancer cells to the tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. This apoptosis induced by the combination of curcumin and TRAIL is not interrupted by Bcl-2 overexpression. We found that treatment with curcumin significantly induces death receptor 5 (DR5) expression both at its mRNA and protein levels, accompanying the generation of the reactive oxygen species (ROS). Not only the pretreatment with N-acetylcystine but also the ectopic expression of peroxiredoxin II, an antioxidative protein, dramatically inhibited the apoptosis induced by curcumin and TRAIL in combination, blocking the curcumin-mediated DR5 upregulation. Taken together, the present study demonstrates that curcumin enhances TRAIL-induced apoptosis by ROS-mediated DR5 upregulation.

Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane)

“…Our results are in agreement with previous findings suggesting that ROS are needed for the apoptotic effects of curcumin [18,[58][59][60][61][62]. Indeed, we found that depletion of endogenous GSH augmented curcumin-induced cell death in tumor cells.…”

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

“…It has also been reported that oxidative stress plays a key role as a mediator of cell death [52]. ROS generation has been proposed to be involved in the upregulation of DR5 by numerous chemopreventive agents, including curcumin [53] and guggulsterone [54]. In the current study, we also observed that emodin induces the upregulation of DR5 through the production of ROS.…”

LY303511 amplifies TRAIL-induced apoptosis in tumor cells by enhancing DR5 oligomerization, DISC assembly, and mitochondrial permeabilization

“…35,39 However, in our model, although LY30 and TRAIL induced an increase in intracellular H 2 O 2 (Supplementary Figure S2A) Figure S2B and C) nor the addition of exogenous H 2 O 2 (data not shown), had any significant effect on LY30-induced sensitization to TRAIL. These data argue against the direct involvement of LY30-mediated intracellular production of H 2 O 2 in DR5 oligomerization and DISC assembly and suggest the involvement of death amplification pathways that may operate in parallel or independent of H 2 O 2 production.…”

“…A second possible candidate could be intracellular H 2 O 2 produced upon LY30 þ TRAIL treatment as various studies have implicated intracellular reactive oxygen species (ROS) in receptor-mediated apoptosis, 35,38 and offer ROS-dependent mechanistic explanations such as release of Smac/Diablo from the mitochondria and ROSinduced death receptor upregulation. 35,39 However, in our model, although LY30 and TRAIL induced an increase in intracellular H 2 O 2 (Supplementary Figure S2A) Figure S2B and C) nor the addition of exogenous H 2 O 2 (data not shown), had any significant effect on LY30-induced sensitization to TRAIL.…”