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Holoch PA, Griffith TS.. TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies. Eur J Pharmacol 625: 63-72

Department of Urology, University of Iowa, 375 Newton Road, Iowa City, IA 52242, USA.
European journal of pharmacology (Impact Factor: 2.53). 10/2009; 625(1-3):63-72. DOI: 10.1016/j.ejphar.2009.06.066
Source: PubMed

ABSTRACT

Since its discovery in 1995, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor super family, has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. Consequently, activation of the apoptotic signaling pathway from the death-inducing TRAIL receptors provides an attractive, biologically-targeted approach to cancer therapy. A great deal of research has focused on deciphering the TRAIL receptor signaling cascade and intracellular regulation of this pathway, as many human tumor cells possess mechanisms of resistance to TRAIL-induced apoptosis. This review focuses on the current state of knowledge regarding TRAIL signaling and resistance, the preclinical development of therapies targeted at TRAIL receptors and modulators of the pathway, and the results of clinical trials for cancer treatment that have emerged from this base of knowledge. TRAIL-based approaches to cancer therapy vary from systemic administration of recombinant, soluble TRAIL protein with or without the combination of traditional chemotherapy, radiation or novel anti-cancer agents to agonistic monoclonal antibodies directed against functional TRAIL receptors to TRAIL gene transfer therapy. A better understanding of TRAIL resistance mechanisms may allow for the development of more effective therapies that exploit this cell-mediated pathway to apoptosis.

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    • "Unfortunately, many tumor cells are resistant against TRAIL-induced apoptosis either intrinsically and/or via various anti-apoptotic signals from the tumor microenvironment. The increased expression of anti-apoptotic proteins such as Bcl-XL, cFLIP, or XIAP and the reduced expression of pro-apoptotic molecules such as caspases and Bid are just some examples of such protective signals[13]. Since TRAIL-induced necroptosis relies on completely distinct molecular pathways, it may therefore represent an effective alternative method to selectively eliminate these cancer cells141516. "
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    ABSTRACT: One hallmark of cancer cells is their ability to evade physiologic signals causing regulated cell death (RCD). Correspondingly, TRAIL-based therapies to eliminate human cancer cells via enforced induction of apoptosis have been established and represent a promising approach in anti-cancer research. However, due to frequently appearing intrinsic or acquired resistances of tumor cells against apoptosis, TRAIL-based apoptotic strategies for the treatment of cancer patients have shown limited efficacy. As a potential alternative, regulated necrosis (and necroptosis triggered e.g. by TRAIL receptors 1/2) has recently gained considerable attention. Regulated necrosis represents a mode of RCD molecularly distinct from apoptosis whose potential in anti-cancer therapy is almost uncharacterized. Since in most cancer cells survival pathways counteract the effects of TRAIL-induced RCD, sensitizers such as cycloheximide (CHX) are frequently added in cell culture to overcome this problem. Unfortunately, those sensitizers are cytotoxic and therefore not suitable for the treatment of cancer patients. Here, we have alternatively employed homoharringtonine (HHT), a plant alkaloid which was recently approved by the U. S. Food and Drug Administration to treat patients with chronic myeloid lymphoma. We show that HHT is an efficient sensitizer for TRAIL-induced necroptosis in multiple human cancer cell lines. In addition, HHT-enhanced TRAIL-mediated necroptosis occurs via the same signaling pathways (involving RIPK1/RIPK3/MLKL) as CHX-enhanced necroptosis. Importantly, consecutive treatment schedules of necroptosis and apoptosis in either combination revealed remarkable additive effects not reached by repetitive apoptotic treatments alone. Taken together, our data demonstrate that HHT can replace harmful substances such as CHX to sensitize human cancer cells to TRAIL-induced necroptosis. Thus, HHT represents a promising enhancer in TRAIL-based necroptotic anti-cancer therapies also in patients.
    Full-text · Article · Apr 2015 · Cell Communication and Signaling
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    • "We observed that induction of miR-139-5p mediated apoptosis occurs by the modulation of extrinsic apoptosis pathway. Apoptosis induced by extrinsic pathways has been considered to be an important antitumor mechanism [30-32]. After transfection with miR-139-5p, the protein expression of the downstream active apoptosis executors caspase-8, caspase-7, caspase-3 was upregulated and enhanced level of cleaved PARP indicated caspase 3 was functionally active (Figure 3D). "
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    ABSTRACT: Background miR-139-5p was identified to be significantly down-regulated in colon tumor tissues by miRNA array. We aimed to clarify its biological function, molecular mechanisms and direct target gene in colorectal cancer (CRC). Methods The biological function of miR-139-5p was examined by cell growth, cell cycle and apoptosis analysis in vitro and in vivo. miR-139-5p target gene and signaling pathway was identified by luciferase activity assay and western blot. Results miR-139-5p was significantly down-regulated in primary tumor tissues (P < 0.0001). Ectopic expression of miR-139-5p in colon cancer cell lines significantly suppressed cell growth as evidenced by cell viability assay (P < 0.001) and colony formation assay (P < 0.01) and in xenograft tumor growth in nude mice (P < 0.01). miR-139-5p induced apoptosis (P < 0.01), concomitantly with up-regulation of key apoptosis genes including cleaved caspase-8, caspase-3, caspase-7 and PARP. miR-139-5p also caused cell cycle arrest in G0/G1 phase (P < 0.01), with upregulation of key G0/G1 phase regulators p21Cip1/Waf1 and p27Kip1. Moreover, miR-139-5p inhibited cellular migration (P < 0.001) and invasiveness (P < 0.001) through the inhibition of matrix metalloproteinases (MMP)7 and MMP9. Oncogene NOTCH1 was revealed to be a putative target of miR-139-5p, which was inversely correlated with miR-139-5p expression (r = -0.3862, P = 0.0002). Conclusions miR-139-5p plays a pivotal role in colon cancer through inhibiting cell proliferation, metastasis, and promoting apoptosis and cell cycle arrest by targeting oncogenic NOTCH1.
    Full-text · Article · May 2014 · Molecular Cancer
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    • "HVJ-E-mediated cell growth inhibition of PC3 was suppressed by the knockdown of RIG-I and MAVS, indicating that the RIG-I/MAVS signaling pathway is important for this process. Moreover, HVJ-E treatment induced the expression of TRAIL and Noxa (known as apoptosis inducers [98, 99]) in PC3 and DU145 cells, but not in PNT2 cells, via RIG-I/MAVS signaling. The fact that the knockdown of TRAIL and Noxa suppressed the HVJ-E sensitivity of PC3 and DU145, respectively, indicates that these apoptosis inducers are responsible for HVJ-E-induced cancer cell apoptosis. "
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    Full-text · Article · Dec 2013
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