Intracellular localization of DR5 and related regulatory pathways as a mechanism of resistance to TRAIL in cancer

TNF-related apoptosis-inducing ligand (TRAIL) is a prominent cytokine capable of inducing apoptosis. It can bind to five different cognate receptors, through which diverse intracellular pathways can be activated. TRAIL’s ability to preferentially kill transformed cells makes it a promising potential weapon for targeted tumor therapy. However, recognition of several resistance mechanisms to TRAIL-induced apoptosis has indicated that a thorough understanding of the details of TRAIL biology is still essential before this weapon can be confidently unleashed. Critical to this aim is revealing the functions and regulation mechanisms of TRAIL’s potent death receptor DR5. Although expression and signaling mechanisms of DR5 have been extensively studied, other aspects, such as its subcellular localization, non-signaling functions, and regulation of its membrane transport, have only recently attracted attention. Here, we discuss different aspects of TRAIL/DR5 biology, with a particular emphasis on the factors that seem to influence the cell surface expression pattern of DR5, along with factors that lead to its nuclear localization. Disturbance of this balance apparently affects the sensitivity of cancer cells to TRAIL-mediated apoptosis, thus constituting an eligible target for potential new therapeutic agents.     

TRAIL promotes the survival,migration and proliferation of vascular smooth muscle cells

Human and rat primary sub-cultured vascular smooth muscle cells (VSMCs) showed clear expression of the death receptors TRAIL-R1 and TRAIL-R2; however, recombinant soluble TRAIL did not induce cell death when added to these cells. TRAIL tended to protect rat VSMCs from apoptosis induced either by inflammatory cytokines tumor necrosis factor- + interleukin-1 + interferon- or by prolonged serum withdrawal, and promoted a significant increase in VSMC proliferation and migration. Of note, all the biological effects induced by TRAIL were significantly inhibited by pharmacological inhibitors of the ERK pathway. Western blot analysis consistently showed that TRAIL induced a significant activation of ERK1/2, and a much weaker phosphorylation of Akt, while it did not affect the p38/MAPK pathway. Taken together, these data strengthen the notion that the TRAIL/TRAIL-R system likely plays a role in the biology of the vascular system by affecting the survival, migration and proliferation of VSMCs.Received 6 May 2004; received after revision 7 June 2004; accepted 8 June 2004     

Role of full-length osteoprotegerin in tumor cell biology

Osteoprotegerin (OPG) is a soluble tumor necrosis factor receptor family member, which potently inhibits RANKL-mediated osteoclastogenesis. Numerous constructs have been created for therapeutic purposes in which the heparin-binding and death homology domains of OPG were removed and the remaining peptide (amino acids 22–194) was fused to the Fc domain of human IgG1 (OPG-Fc). The administration of OPG-Fc efficiently counteracted bone loss in a variety of preclinical models of cancers. However, several in vitro studies have shown that native or recombinant full-length OPG not only neuralizes RANKL, but also the death-inducing ligand TRAIL, suggesting that OPG might potentially counteract the anti-tumor activity of TRAIL. Additional evidence suggests that full-length OPG possesses RANKL- and TRAIL-independent biological properties, mainly related to the promotion of endothelial cell survival and angiogenesis. Finally, breast tumor cells overexpressing OPG have shown increased bone metastatic potential in vivo. The relevance of these apparently conflicting findings in tumor cell biology is highlighted. Received 2 September 2008; received after revision 29 September 2008; accepted 13 October 2008     

Combining naturally occurring polyphenols with TNF-related apoptosis-inducing ligand: a promising approach to kill resistant cancer cells?

TNF-related apoptosis-inducing ligand (TRAIL) and its receptors are attractive targets for anticancer therapy owing to their ability to trigger apoptosis selectively in cancer cells but not in normal cells. To date, many combinatorial strategies, such as chemotherapy or radiotherapy, have given encouraging results for overcoming TRAIL resistance in preclinical models. In this review, we provide an overview of the molecular mechanisms underlying sensitization to TRAIL-induced apoptosis by polyphenols. These naturally occurring compounds can restore tumor cell sensitivity to TRAIL-induced cell death with no apparent toxicity towards normal cells. Both extrinsic and intrinsic pathways can be modulated by polyphenols, the activation of which largely depends on the cell type, the particular polyphenolic compound, and the conditions of treatment. The large variety of polyphenol cellular targets could prove useful in circumventing TRAIL resistance. The relevance of these combined treatments for cancer therapy is discussed in the light of recent preclinical studies.     

TNF-α modulates the migratory response of mesenchymal stem cells to TRAIL

The number of circulating mesenchymal stem cells (MSC), analyzed after acute myocardial infarction (AMI), was lower in AMI patients who developed heart failure (HF) in the follow-up. Conversely, the circulating levels of tumor necrosis factor (TNF)-α, and osteoprotegerin (OPG) were higher in AMI patients who developed HF with respect to the patients who did not develop HF. In vitro exposure to TNF-α enhanced the migration of MSC in response to TNF-related apoptosis-inducing ligand (TRAIL) and significantly increased the release of OPG by endothelial cells. On the contrary, OPG dose-dependently neutralized the in vitro pro-migratory activity of TRAIL. Thus, TNF-α exhibits opposite effects on MSC migration driven by TRAIL: it is capable of potentiating MSC migration as well as of inhibiting MSC migration as an indirect consequence of OPG induction, which might result in a suboptimal recruitment of circulating MSC after AMI in those patients who develop HF in the follow-up.