Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

Pavet, Valeria; Beyrath, Julien; Pardin, Christophe; Morizot, Alexandre; Lechner, Marie-Charlotte; Briand, Jean‐Paul; Wendland, Miriam; Maison, Wolfgang; Fournel, Sylvie; Micheau, Olivier; Guichard, Gilles; Gronemeyer, Hinrich

doi:10.1158/0008-5472.can-09-2889

Cited by 98 publications

(110 citation statements)

References 46 publications

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“…These findings are consistent with the earlier report that resveratrol induces p53-independent apoptosis in cancer cells (65,67,(73)(74)(75)(76). Although Bak can be activated by p53 (59), we did not observe p53 involvement in Bak activation.…”

Section: Discussionsupporting

confidence: 93%

“…Because resveratrol primarily targets mitochondria to induce apoptosis, resveratrol could be used as a synergistic agent to enhance death receptor-mediated cancer cell death. Indeed, elegant works of other colleagues have demonstrated that resveratrol enhances TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in cancer cells (67)(68)(69)(70).…”

Section: Discussionmentioning

confidence: 99%

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Resveratrol Induces p53-independent, X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Bax Protein Oligomerization on Mitochondria to Initiate Cytochrome c Release and Caspase Activation

Gogada¹,

Prabhu²,

Amadori

et al. 2011

Journal of Biological Chemistry

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Resveratrol, a naturally occurring phytoalexin, is known to induce apoptosis in multiple cancer cell types, but the underlying molecular mechanisms remain unclear. Here, we show that resveratrol induced p53-independent, X-linked inhibitor of apoptosis protein (XIAP)-mediated translocation of Bax to mitochondria where it underwent oligomerization to initiate apoptosis. Resveratrol treatment promoted interaction between Bax and XIAP in the cytosol and on mitochondria, suggesting that XIAP plays a critical role in the activation and translocation of Bax to mitochondria. This process did not involve p53 but required accumulation of Bim and t-Bid on mitochondria. Bax primarily underwent homo-oligomerization on mitochondria and played a major role in release of cytochrome c to the cytosol. Bak, another key protein that regulates the mitochondrial membrane permeabilization, did not interact with p53 but continued to associate with Bcl-xL. Thus, the proapoptotic function of Bak remained suppressed during resveratrol-induced apoptosis. Caspase-9 silencing inhibited resveratrol-induced caspase activation, whereas caspase-8 knockdown did not affect caspase activity, suggesting that resveratrol induces caspase-9-dependent apoptosis. Together, our findings characterize the molecular mechanisms of resveratrol-induced caspase activation and subsequent apoptosis in cancer cells.Anticancer agents induce cell death in cancer and normal cells via mechanisms including apoptosis and autophagy (1-4). Therefore, there is a need for alternative anticancer agents that can promote cancer cell death while avoiding killing of normal, non-cancerous cells. Resveratrol (trans-3,5,4Ј-trihydroxystilbene) is a naturally occurring polyphenolic phytoalexin found at high levels in the skin of grapes and in red wine. It is also present in peanuts and other plant products. Resveratrol has been shown to possess an apoptosis-dependent anticancer activity and minimal toxicity to normal cells (5-11). How resveratrol induces apoptosis or cancer cell death is not clearly known, but available evidence indicates that resveratrol induces p53-dependent signaling, which leads to cell cycle arrest and apoptosis induction (10, 12, 13). Additionally, resveratrol targets mitochondria to induce cytochrome c release and thereby triggers caspase-dependent apoptotic cell death in multiple types of cancer cells (14 -18). How resveratrol induces cytochrome c release and caspase activation to execute apoptosis remains unclear.Caspases are activated by proteolytic processing and are broadly divided into initiator caspases (e.g. procaspase-8 and -9) and executioner caspases (such as procaspase-3 and -7) (19 -22). During apoptosis, the released cytochrome c from mitochondria triggers caspase-9 activation, whereas ligation of death receptors on the plasma membrane activates caspase-8. Active caspase-8 generated upon death receptor ligation requires Bid-mediated cytochrome c release to execute apoptotic cell death in epithelial cancer cells (22)(23)(24)(25). Proapoptotic BH3-o...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Resveratrol Induces p53-independent, X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Bax Protein Oligomerization on Mitochondria to Initiate Cytochrome c Release and Caspase Activation

Gogada¹,

Prabhu²,

Amadori

et al. 2011

Journal of Biological Chemistry

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“…Preclinical studies and clinical trials are giving promising results, supporting the potential of these combining approaches. 17,18 Cell surface expression of TRAIL agonistic receptors is the first requirement in order to trigger the TRAIL apoptotic machinery but, to date, the expression of TRAIL receptors in primary tumors remains poorly studied and the anti-apoptotic function of TRAIL-R4 remains controversial. It was found, however, in a few studies that primary lymphomas could express functional TRAIL antagonistic receptors at the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level

et al. 2010

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“…In addition to agonistic antibodies, the development of other biologic mimetics of TRAIL has been reported, this including oligomeric forms of TRAIL receptor-binding peptides (20,21) and scaffold proteins (22,23). An ideal therapeutic that activates the TRAILR2 pathway would combine the potency of the natural ligand with the favorable manufacturing attributes of antibodies.…”

Section: Introductionmentioning

confidence: 99%

Multivalent Scaffold Proteins as Superagonists of TRAIL Receptor 2–Induced Apoptosis

Swers¹,

Grinberg²,

Wang³

et al. 2013

Molecular Cancer Therapeutics

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Activation of TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) can induce apoptosis in a variety of human cancer cell lines and xenografts, while lacking toxicity in normal cells. The natural ligand and agonistic antibodies show antitumor activity in preclinical models of cancer, and this had led to significant excitement in the clinical potential of these agents. Unfortunately, this optimism has been tempered by trial data that, thus far, are not showing clear signs of efficacy in cancer patients. The reasons for discrepant preclinical and clinical observations are not understood, but one possibility is that the current TRAILR2 agonists lack sufficient potency to achieve a meaningful response in patients. Toward addressing that possibility, we have developed multivalent forms of a new binding scaffold (Tn3) that are superagonists of TRAILR2 and can induce apoptosis in tumor cell lines at subpicomolar concentrations. The monomer Tn3 unit was a fibronectin type III domain engineered for high-affinity TRAILR2 binding. Multivalent presentation of this basic unit induced cell death in TRAILR2-expressing cell lines. Optimization of binding affinity, molecular format, and valency contributed to cumulative enhancements of agonistic activity. An optimized multivalent agonist consisting of 8 tandem Tn3 repeats was highly potent in triggering cell death in TRAIL-sensitive cell lines and was 1 to 2 orders of magnitude more potent than TRAIL. Enhanced potency was also observed in vivo in a tumor xenograft setting. The TRAILR2 superagonists described here have the potential for superior clinical activity in settings insensitive to the current therapeutic agonists that target this pathway.

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Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

Cited by 98 publications

References 46 publications

Resveratrol Induces p53-independent, X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Bax Protein Oligomerization on Mitochondria to Initiate Cytochrome c Release and Caspase Activation

Resveratrol Induces p53-independent, X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Bax Protein Oligomerization on Mitochondria to Initiate Cytochrome c Release and Caspase Activation

Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level

Multivalent Scaffold Proteins as Superagonists of TRAIL Receptor 2–Induced Apoptosis

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