Sulforaphane enhances TRAIL-induced apoptosis through the induction of DR5 expression in human osteosarcoma cells

Matsui, Takaaki; Sowa, Yoshihiro; Yoshida, Tatsushi; Murata, Hiroaki; Horinaka, Mano; Wakada, Miki; Nakanishi, Ryoko; Sakabe, Tomoya; Kubo, Toshikazu

doi:10.1093/carcin/bgl015

Cited by 52 publications

(43 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Resultscontrasting

confidence: 53%

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

et al. 2007

View full text Add to dashboard Cite

Certain classes of tumor cells respond favorably to TRAIL due to the presence of cell surface death receptors DR4 and DR5. Despite this preferential sensitivity, resistance to TRAIL remains a clinical problem and therefore the heightened interest in identifying compounds to revert tumor sensitivity to TRAIL. We recently demonstrated that the phosphatidylinositide-3-kinase (PI3K) inhibitor, LY294002, and its inactive analog LY303511, sensitized tumor cells to vincristine-induced apoptosis, independent of PI3K/Akt pathway. Intrigued by these findings, we investigated the effect of LY303511 on TRAIL-induced apoptosis in HeLa cells. Preincubation of cells with LY30 significantly amplified TRAIL signaling as evidenced by enhanced DNA fragmentation, caspases 2, 3, 8, and 9 activation, and reduction in the tumor colony formation. This increase in TRAIL sensitivity involved mitochondrial membrane permeabilization resulting in the egress of cytochrome c and second mitochondrial activator of caspase/direct IAP-binding protein with low PI, cleavage of X-linked inhibitor of apoptosis protein, and activation of caspase 9. We link this execution signal to the ability of LY30 to downregulate cFLIP S and oligomerize DR5, thus facilitating the signaling of the death initiating signaling complex. The subsequent exposure to TRAIL resulted in processing/activation of caspase 8 and cleavage of its substrate, the BH3 protein Bid. These data provide a novel mechanism of action of this small molecule with the potential for use in TRAIL-resistant tumors. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis preferentially in tumor cells. 1,2 The selective responsiveness of TRAIL is attributed to the increased surface expression of TRAIL receptors (DR4 and DR5) on tumor cells. [3][4][5][6] In contrast, nontransformed cells express decoy receptors that provide a mechanism for evading apoptotic signaling initiated by TRAIL, and hence its tumor selectivity. 7,8 Unfortunately, as with most chemotherapeutic compounds, TRAIL-responsive tumors acquire a resistant phenotype which renders TRAIL therapy ineffective. 9,10 This has stimulated an enormous interest in identifying small molecule compounds that, when used in combination with TRAIL could sensitize tumor cells to TRAILinduced apoptosis. The desired consequence would be the need for a much lower therapeutic dose of TRAIL and at the same time an increase in the efficacy of the sensitizing drug. To that end, various groups have demonstrated that a variety of compounds and proteins (either upon silencing or upregulation) sensitize several classes of tumor cells to TRAIL-induced apoptosis. 11,12 LY303511 (LY30) is an inactive analog of LY294002 (LY29), a widely used inhibitor of the phosphatidylinositide-3-kinase (PI3K)/Akt survival pathway. 13 Previously, LY30 has been purported to have no effect on cells in contrast to its active counterpart, LY29. However, recent studies from our laboratory and other groups have demonstrated that LY30 does have a...

show abstract

Section: Resultscontrasting

confidence: 53%

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

et al. 2007

View full text Add to dashboard Cite

show abstract

“…SFN could sensitize cells to apoptosis through upregulation of death receptors (83,84). It was found that SFN enhanced TRAIL-induced apoptosis in human osteosarcoma cells (Saos2 and MG63) and hepatoma cells.…”

Section: Receptors As Molecular Targets For Peitc and Sfnmentioning

confidence: 99%

Molecular Targets of Dietary Phenethyl Isothiocyanate and Sulforaphane for Cancer Chemoprevention

Cheung

Kong

2009

AAPS J

319

288

View full text Add to dashboard Cite

Abstract. Development of cancer is a long-term and multistep process which comprises initiation, progression, and promotion stages of carcinogenesis. Conceivably, it can be targeted and interrupted along these different stages. In this context, many naturally occurring dietary compounds from our daily consumption of fruits and vegetables have been shown to possess cancer preventive effects. Phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) are two of the most widely investigated isothiocyanates from the crucifers. Both have been found to be very potent chemopreventive agents in numerous animal carcinogenesis models as well as cell culture models. They exert their chemopreventive effects through regulation of diverse molecular mechanisms. In this review, we will discuss the molecular targets of PEITC and SFN potentially involved in cancer chemoprevention. These include the regulation of drugmetabolizing enzymes phase I cytochrome P450s and phase II metabolizing enzymes. In addition, the signaling pathways including Nrf2-Keap 1, anti-inflammatory NFκB, apoptosis, and cell cycle arrest as well as some receptors will also be discussed. Furthermore, we will also discuss the similarities and their potential differences in the regulation of these molecular targets by PEITC and SFN.

show abstract

“…Importantly, sulforaphane neither induces DR5 protein expression nor enhances TRAIL-induced apoptosis in normal human peripheral blood mononuclear cells. 117 Luteolin (Fig. 2), a naturally occurring flavonoid, induces apoptosis in various cancer cells.…”

Section: Modulation Of Death Receptor Expression By Cancer Therapeutimentioning

confidence: 99%

Modulation of death receptors by cancer therapeutic agents

Elrod

Sun²

2008

Cancer Biology & Therapy

106

View full text Add to dashboard Cite

Sulforaphane enhances TRAIL-induced apoptosis through the induction of DR5 expression in human osteosarcoma cells

Cited by 52 publications

References 37 publications

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

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

Molecular Targets of Dietary Phenethyl Isothiocyanate and Sulforaphane for Cancer Chemoprevention

Modulation of death receptors by cancer therapeutic agents

Contact Info

Product

Resources

About