TRAIL-induced apoptosis of FHIT-negative lung cancer cells is inhibited by FHIT re-expression.
Mirandola Prisco,Gobbi Giuliana,Sponzilli Ivonne,Malinverno Chiara,Cavazzoni Andrea,Alfieri Roberta,Petronini Pier Giorgio,Vitale Marco
Journal of cellular physiology
Fragile histidine triad (FHIT) is a tumor suppressor gene whose allelic loss is associated to a number of human cancers. FHIT protein acts as a diadenosine oligophosphate hydrolase, but its tumor suppressive activity appears as independent from its enzymatic activity. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) can induce apoptosis in the FHIT-negative non-small lung cancer cell line Calu-1. We generated four FHIT-inducible Calu-1 cell clones and demonstrated that FHIT expression was able to protect cells from TRAIL-induced apoptosis, without affecting TRAIL-receptors surface expression. FHIT-specific small interference RNA transfection of SV40-immortalized normal bronchial BEAS cells that show levels of FHIT protein comparable to those of normal bronchial cells, resulted in a significant increase of TRAIL-induced apoptosis. Of note, suramin-mediated inhibition of FHIT enzymatic activity also enhanced TRAIL-induced apoptosis. We conclude that FHIT expression in lung cancer cells is protective from TRAIL-induced apoptosis. Our data suggest that FHIT exerts this protective effect downstream TRAIL-receptors and likely requires its dinucleoside-triphosphate hydrolase activity. As TRAIL represents in the near future a good candidate for death ligands-based anticancer therapy, its potential therapeutic use should be envisaged as preliminary to molecular genetics interventions or drug-induced epigenetic modulations aimed to restoring FHIT gene expression levels in non-small cells lung tumors.
10.1002/jcp.21801
The combination of TRAIL and the Smac mimetic LCL-161 induces an irreversible phenotypic change of MCF-7 breast cancer cells.
Experimental and molecular pathology
INTRODUCTION:Breast cancer is the most common malignancy affecting women. Although the prognosis generally is good, a substantial number of patients still suffer from relapse, emphasizing the need for novel treatments. Smac mimetics were developed to facilitate cell death by blocking inhibitor of apoptosis proteins (IAPs). It has been suggested that TNF-related apoptosis inducing ligand (TRAIL) can be used together with Smac mimetics to induce cancer cell death. METHODS:Cell viability was studied with Trypan blue staining and Annexin V assay, siRNA was used to downregulate specific proteins, protein levels were estimated with Western blot, and mRNA levels were analyzed with qPCR, microarray and RNA-seq. For global expression, groups were compared with principal component analysis and the limma package in R. Gene enrichment was analyzed with Fisher's test. For other experiments, significance of difference was tested by one-way ANOVA, followed by Tukey's HSD test. RESULTS:The combination of Smac mimetic LCL-161 and TRAIL induces an irreversible change in phenotype, but not cell death, of luminal MCF-7 breast cancer cells. The cells become small and circular and dissociate from each other and the effect could not be reversed by returning the cells to regular growth medium. The morphology change could be prevented by caspase inhibition using z-VAD-FMK and downregulation of caspase-8. Caspase-7 is also indicated to be of importance since downregulation of this caspase resulted in fewer morphologically changed cells. Enrichment analyses of changes in global gene expression demonstrated that genes associated with estrogen receptor (ER) signaling are downregulated, whereas nuclear factor kappa B- (NF-κB) and interferon- (IFN) driven genes are upregulated in altered cells. However, inhibition of these pathways did not influence the change in morphology. Induction of IFN-induced genes were potentiated but NF-ĸB-driven genes were slightly suppressed by caspase inhibition. CONCLUSIONS:The results demonstrate that LCL-161 and TRAIL can irreversibly alter the MCF-7 breast cancer cell phenotype. However, the changes in morphology and global gene expression are mediated via separate pathways.
10.1016/j.yexmp.2021.104739
Endogenous TRAIL-R4 critically impacts apoptotic and non-apoptotic TRAIL-induced signaling in cancer cells.
Frontiers in cell and developmental biology
Binding of TRAIL to its death domain-containing receptors TRAIL-R1 and TRAIL-R2 can induce cell death and/or pro-inflammatory signaling. The importance of TRAIL and TRAIL-R1/R2 in tumor immune surveillance and cancer biology has meanwhile been well documented. In addition, TRAIL has been shown to preferentially kill tumor cells, raising hope for the development of targeted anti-cancer therapies. Apart from death-inducing receptors, TRAIL also binds to TRAIL-R3 and TRAIL-R4. Whereas TRAIL-R3 is lacking an intracellular domain entirely, TRAIL-R4 contains a truncated death domain but still a signaling-competent intracellular part. It is assumed that these receptors have anti-apoptotic, yet still not well understood regulatory functions. To analyze the significance of the endogenous levels of TRAIL-R4 for TRAIL-induced signaling in cancer cells, we stably knocked down this receptor in Colo357 and MDA-MB-231 cells and analyzed the activation of apoptotic and non-apoptotic pathways in response to treatment with TRAIL. We found that TRAIL-R4 affects a plethora of signaling pathways, partly in an opposite way. While knockdown of TRAIL-R4 in Colo357 strongly increased apoptosis and reduced clonogenic survival, it inhibited cell death and improved clonogenic survival of MDA-MB-231 cells after TRAIL treatment. Furthermore, TRAIL-R4 turned out to be an important regulator of the expression of a variety of anti-apoptotic proteins in MDA-MB-231 cells since TRAIL-R4-KD reduced the cellular levels of FLIPs, XIAP and cIAP2 but upregulated the levels of Bcl-xL. By inhibiting Bcl-xL with Navitoclax, we could finally show that this protein mainly accounts for the acquired resistance of MDA-MB-231 TRAIL-R4-KD cells to TRAIL-induced apoptosis. Analyses of non-apoptotic signaling pathways revealed that in both cell lines TRAIL-R4-KD resulted in a constitutively increased activity of AKT and ERK, while it reduced AKT activity after TRAIL treatment. Furthermore, TRAIL-R4-KD potentiated TRAIL-induced activation of ERK and p38 in Colo357, and NF-κB in MDA-MB-231 cells. Importantly, in both cell lines the activity of AKT, ERK, p38 and NF-κB after TRAIL treatment was higher in TRAIL-R4-KD cells than in respective control cells. Thus, our data provide evidence for the important regulatory functions of endogenous TRAIL-R4 in cancer cells and improve our understanding of the very complex human TRAIL/TRAIL-R system.
10.3389/fcell.2022.942718
Postdiagnosis circulating osteoprotegerin and TRAIL concentrations and survival and recurrence after a breast cancer diagnosis: results from the MARIE patient cohort.
Breast cancer research : BCR
BACKGROUND:Experimental studies suggest a role for osteoprotegerin (OPG) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in mammary tumor development and progression. These biomarkers have been minimally investigated with respect to outcomes in breast cancer patients. METHODS:OPG and TRAIL were evaluated in blood samples collected from 2459 breast cancer patients enrolled in the MARIE study, a prospective population-based patient cohort, at median of 129 days after diagnosis. Participants were between ages 50 and 74 at diagnosis and recruited from 2002 to 2005 in two regions of Germany. Follow-up for recurrence and mortality was conducted through June 2015. Delayed-entry Cox proportional hazards regression was used to assess associations between OPG and TRAIL with all-cause and breast cancer-specific mortality, and recurrence, both overall and by tumor hormone receptor status. RESULTS:Median follow-up time was 11.7 years, with 485 deaths reported (277 breast cancer-specific). Higher OPG concentrations were associated with a higher risk of all-cause mortality (hazard ratio for 1-unit log2-transformed concentration (HR) = 1.24 (95% confidence interval 1.03-1.49). Associations were observed in women diagnosed with ER-PR- tumors or discordant hormone receptor status (ER-PR-, HR = 1.93 (1.20-3.10); discordant ERPR, 1.70 (1.03-2.81)), but not for women with ER + PR + tumors (HR = 1.06 (0.83-1.35)). OPG was associated with a higher risk of recurrence among women with ER-PR- disease (HR = 2.18 (1.39-3.40)). We observed no associations between OPG and breast cancer-specific survival, or for TRAIL and any outcome. CONCLUSIONS:Higher circulating OPG may be a biomarker of a higher risk of poor outcome among women diagnosed with ER- breast cancer. Further mechanistic studies are warranted.
10.1186/s13058-023-01625-4
Breathing New Life into TRAIL for Breast Cancer Therapy: Co-Delivery of pTRAIL and Complementary siRNAs Using Lipopolymers.
Thapa Bindu,Kc Remant,Bahniuk Markian,Schmitke Janine,Hitt Mary,Lavasanifar Afsaneh,Kutsch Olaf,Seol Dai-Wu,Uludag Hasan
Human gene therapy
Preclinical studies showed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy is safe and effective to combat cancers, but clinical outcomes have been less than optimal due to short half-life of TRAIL protein, insufficient induction of apoptosis, and TRAIL resistance displayed in many tumors. In this study, we explored co-delivery of a TRAIL expressing plasmid (pTRAIL) and complementary small interfering RNAs (siRNAs) (silencing [BCL2L12] and [SOD1]) to improve the response of breast cancer cells against TRAIL therapy. It is desirable to co-deliver the pDNA along with siRNA using a single delivery agent, but this is challenging given different structures of long/flexible pDNA and short/rigid siRNA. Toward this goal, we identified an aliphatic lipid-grafted low-molecular weight polyethylenimine (PEI) that accommodated both pDNA and siRNA in a single complex. The co-delivery of pTRAIL with BCL2L12- or SOD1-specific siRNAs resulted more significant cell death in different breast cancer cells compared with separate delivery without affecting nonmalignant cells viability. Ternary complexes of lipopolymer with pTRAIL and BCL2L12 siRNA significantly retarded the growth of breast cancer xenografts in mice. The enhanced anticancer activity was attributed to increased secretion of TRAIL and sensitization of breast cancer cells against TRAIL by the co-delivered siRNAs. The lipid-grafted PEIs capable of co-delivering multiple types of nucleic acids can serve as powerful carriers for more effective complementary therapeutics. Graphical Abstract [Figure: see text].
10.1089/hum.2019.096
Daurisoline inhibits proliferation, induces apoptosis, and enhances TRAIL sensitivity of breast cancer cells by upregulating DR5.
Cell biology international
Daurisoline (DS) is an isoquinoline alkaloid that exerts anticancer activities in various cancer cells. However, the underlying mechanisms through which DS affects the survival of breast cancer cells remain poorly understood. Therefore, the present study was undertaken to investigate the potential anticancer effect of DS on breast cancer cells and reveal the mechanism underlying the enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by DS. Cell counting kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assay were used to evaluate the ability of cell proliferation. Flow cytometry was selected to examine the cell cycle distribution. TUNEL assay was used to detect the cell apoptosis. The protein expression was measured by Western blot analysis. DS was found to reduce the cell viability and suppress the proliferation of MCF-7 and MDA-MB-231 cells by causing G1 phase cell cycle arrest. DS could trigger apoptosis by promoting the cleavage of caspase-8 and PARP. The phosphorylation of ERK, JNK, and p38MAPK was upregulated clearly following DS treatment. Notably, SP600125 (JNK inhibitor) pretreatment significantly abrogated DS-induced PARP cleavage. DS inactivated Akt/mTOR and Wnt/β-catenin signaling pathway and upregulated the expression of ER stress-related proteins. Additionally, DS amplified TRAIL-caused viability reduction and apoptosis in breast cancer cells. Mechanismly, DS upregulated the protein level of DR4 and DR5, and knockdown of DR5 attenuated the cotreatment-induced cleavage of PARP. Inhibition of JNK could block DS-induced upregulation of DR5. This study provides valuable insights into the mechanisms of DS inhibiting cell proliferation, triggering apoptosis, and enhancing TRAIL sensitivity of breast cancer cells.
10.1002/cbin.12162
TRAIL-Induced Apoptosis in TRAIL-Resistant Breast Carcinoma Through Quercetin Cotreatment.
Manouchehri Jasmine M,Turner Katherine A,Kalafatis Michael
Breast cancer : basic and clinical research
Breast cancer is the most commonly diagnosed cancer in women. There is a continued interest for the development of more efficacious treatment regimens for breast carcinoma. Recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) shows potential as a potent anticancer therapeutic for the treatment of breast cancer, whereas displaying minimal toxicity to normal cells. However, the promise of rhTRAIL for the treatment of breast cancer is dismissed by the resistance to rhTRAIL-induced apoptosis exhibited by many breast cancers. Thus, a cotreatment strategy was examined by applying the natural compound quercetin (Q) as a sensitizing agent for rhTRAIL-resistant breast cancer BT-20 and MCF-7 cells. Quercetin was able to sensitize rhTRAIL-resistant breast cancers to rhTRAIL-induced apoptosis as detected by Western blotting through the proteasome-mediated degradation of c-FLIP and through the upregulation of DR5 expression transcriptionally. Overall, these in vitro findings establish that Q is an effective sensitizing agent for rhTRAIL-resistant breast cancers.
10.1177/1178223417749855
The role of the immune response and inflammatory pathways in TNF-related apoptosis-inducing ligand (TRAIL) resistance in triple-negative breast cancer cells.
American journal of cancer research
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, and the majority of TNBC lacks targeted therapies. Previous studies have shown that TNBC cells are highly sensitive to TNF-related apoptosis-inducing ligand (TRAIL), making it a potentially viable treatment option for TNBC. However, the development of TRAIL resistance limits its potential for clinical use, and the underlying mechanisms are not fully understood. To better understand the mechanism of resistance to TRAIL, we performed RNA sequencing to identify the candidates that are responsible for resistance to TRAIL in two previously established TRAIL-resistant MDA231 and SUM159 cells. This approach led us to identify differentially expressed genes (DEGs) and pathways in TRAIL-resistant MDA231 and SUM159 cells compared to their TRAIL-sensitive counterparts. We showed that several DEGs and pathways were associated with inflammation in TRAIL-resistant cells, including IL-1α and IL6. By downregulating IL-1α and IL6 expression, we showed that TRAIL sensitivity can be significantly restored in TRAIL-resistant cells. Therefore, this study identifies a mechanism by which the inflammation pathway promotes TRAIL resistance, which could be targeted for enhancing TRAIL-based therapies in TNBC cells.
Induction of interferon-β and interferon signaling by TRAIL and Smac mimetics via caspase-8 in breast cancer cells.
Granqvist Victoria,Holmgren Christian,Larsson Christer
PloS one
Breast cancer prognosis is frequently good but a substantial number of patients suffer from relapse. The death receptor ligand TRAIL can in combination with Smac mimetics induce apoptosis in some luminal-like ER-positive breast cancer cell lines, such as CAMA-1, but not in MCF-7 cells. Here we show that TRAIL and the Smac mimetic LCL161 induce non-canonical NF-κB and IFN signaling in ER-positive MCF-7 cells and in CAMA-1 breast cancer cells when apoptosis is blocked by caspase inhibition. Levels of p52 are increased and STAT1 gets phosphorylated. STAT1 phosphorylation is induced by TRAIL alone in MCF-7 cells and is independent of non-canonical NF-κB since downregulation of NIK has no effect. The phosphorylation of STAT1 is a rather late event, appearing after 24 hours of TRAIL stimulation. It is preceded by an increase in IFNB1 mRNA levels and can be blocked by siRNA targeting the type I IFN receptor IFNAR1 and by inhibition of Janus kinases by Ruxolitinib. Moreover, downregulation of caspase-8, but not inhibition of caspase activity, blocks TRAIL-mediated STAT1 phosphorylation and induction of IFN-related genes. The data suggest that TRAIL-induced IFNB1 expression in MCF-7 cells is dependent on a non-apoptotic role of caspase-8 and leads to autocrine interferon-β signaling.
10.1371/journal.pone.0248175
Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells.
Mauro-Lizcano Marta,López-Rivas Abelardo
Cell death & disease
Glutamine plays an important role in the metabolism of tumor cells through its contribution to redox homeostasis, bioenergetics, synthesis of macromolecules, and signaling. Triple-negative breast cancers (TNBC) are highly metastatic and associated with poor prognosis. TNBC cells show a marked dependence on extracellular glutamine for growth. Herein we demonstrate that TNBC cells are markedly sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis upon glutamine deprivation. Upregulation of pro-apoptotic TRAIL receptor 2 (TRAIL-R2/DR5) and downregulation of FLICE-inhibitory protein (FLIP) are observed in glutamine-deprived TNBC cells. Activation of the amino-acid-sensing kinase general control nonderepressible 2 (GCN2) upon glutamine deprivation is responsible for TRAIL-R2 upregulation through a signaling pathway involving ATF4 and CHOP transcription factors. In contrast, FLIP downregulation in glutamine-deprived TNBC occurs by a GCN2-independent mechanism. Importantly, silencing FLIP expression by RNA interference results in a marked sensitization of TNBC cells to TRAIL-induced apoptosis. In addition, pharmacological or genetic inhibition of transaminases increases TRAIL-R2 expression and downregulates FLIP levels, sensitizing TNBC cells to TRAIL. Interestingly, treatment with L-asparaginase markedly sensitizes TNBC cells to TRAIL through its glutaminase activity. Overall, our findings suggest that targeting the glutamine addiction phenotype of TNBC can be regarded as a potential antitumoral target in combination with agonists of proapoptotic TRAIL receptors.
10.1038/s41419-018-0263-0
Dihydroartemisinin-Transferrin Adducts Enhance TRAIL-Induced Apoptosis in Triple-Negative Breast Cancer in a P53-Independent and ROS-Dependent Manner.
Zhou Xinyu,Soto-Gamez Abel,Nijdam Fleur,Setroikromo Rita,Quax Wim J
Frontiers in oncology
Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype independent of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. It has a poor prognosis and high recurrence. Due to its limited treatment options in the clinic, novel therapies are urgently needed. Single treatment with the death receptor ligand TRAIL was shown to be poorly effective. Recently, we have shown that artemisinin derivatives enhance TRAIL-induced apoptosis in colon cancer cells. Here, we utilized transferrin (TF) to enhance the effectiveness of dihydroartemisinin (DHA) in inducing cell death in TNBC cell lines (MDA-MB-231, MDA-MB-436, MDA-MB-468 and BT549). We found that the combination of DHA-TF and the death receptor 5-specific TRAIL variant DHER leads to an increase in DR5 expression in all four TNBC cell lines, while higher cytotoxicity was observed in MDA-MB-231, and MDA-MB-436. All the data point to the finding that DHA-TF stimulates cell death in TNBC cells, while the combination of DHA-TF with TRAIL variants will trigger more cell death in TRAIL-sensitive cells. Overall, DHA-TF in combination with TRAIL variants represents a potential novel combination therapy for triple-negative breast cancer.
10.3389/fonc.2021.789336
Induction of Breast Cancer Cell Apoptosis by TRAIL and Smac Mimetics: Involvement of RIP1 and cFLIP.
Current issues in molecular biology
Smac mimetics are a group of compounds able to facilitate cell death in cancer cells. TNF-related apoptosis-inducing ligand (TRAIL) is a death receptor ligand currently explored in combination with Smac mimetics. The molecular mechanisms determining if the combination treatment results in apoptosis are however not fully understood. In this study, we aimed to shed light on these mechanisms in breast cancer cells. Three breast cancer cell lines, MDA-MB-468, CAMA-1 and MCF-7, were used to evaluate the effects of Smac mimetic LCL-161 and TRAIL using cell death assays and Western blot. The combination treatment induces apoptosis and caspase-8 cleavage in MDA-MB-468 and CAMA-1 but not in MCF-7 cells and downregulation of caspase-8 blocked apoptosis. Downregulation, but not kinase inhibition, of receptor-interacting protein 1 (RIP1) suppressed apoptosis in CAMA-1. Apoptosis is preceded by association of RIP1 with caspase-8. Downregulating cellular FLICE-like inhibitory protein (c-FLIP) resulted in increased caspase cleavage and some induction of apoptosis by TRAIL and LCL-161 in MCF-7. In CAMA-1, c-FLIP depletion potentiated TRAIL-induced caspase cleavage and LCL-161 did not increase it further. Our results lend further support to a model where LCL-161 enables the formation of a complex including RIP1 and caspase-8 and circumvents c-FLIP-mediated inhibition of caspase activation.
10.3390/cimb44100327
Combination Therapy of TRAIL and Thymoquinone Induce Breast Cancer Cell Cytotoxicity-Mediated Apoptosis and Cell Cycle Arrest.
Asian Pacific journal of cancer prevention : APJCP
OBJECTIVE:Cancer is one of the leading causes of mortality in both developed and developing nations. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is characterized by its ability to selectively trigger apoptosis in cancer cells. TRAIL-based interventions have led to the development of recombinant human (rhTRAIL) as a promising therapy for different types of human cancer. Thymoquinone (TQ) has been shown to exert anticancer effect. The aim of the current study is to investigate the anticancer effect of the combinatorial therapy of TRAIL+TQ against human breast cancer cells. METHODS:To achieve this hypothesis, cytotoxicity using MTT assay, as well as apoptosis and cell cycle using flow cytometric technique were preceded against breast cancer MCF-7 and MDA-MB-231 cancerous cell lines. RESULTS:The current study showed that TRAIL induced cell cycle arrest and apoptosis. Moreover, it inhibited proliferation of MDA-MB-231 cells more than MCF-7 cells. Adding TQ to TRAIL increased the chemo-sensitivity of MDA-MB-231, while overcame the MCF-7 resistance to TRAIL. CONCLUSION:In conclusion, there is a synergistic effect between TRAIL and TQ playing a therapeutic role in killing resistant breast cancer cells.
10.31557/APJCP.2021.22.5.1513
Tumor Cell-selective Synergism of TRAIL- and ATRA-induced Cytotoxicity in Breast Cancer Cells.
Reinhardt Annekathrin,Liu Hongyu,Ma Yunxia,Zhou Yongan,Zang Chuanbing,Habbel Jan-Piet,Possinger Kurt,Eucker Jan
Anticancer research
BACKGROUND/AIM:One of the major problems in breast cancer treatment is pharmacoresistance. Therefore, exploration of treatment alternatives is of clinical relevance. The present work focused on tumor cell-inhibiting effects of a combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and all trans retinoic acid (ATRA) in breast cancer cells. MATERIALS AND METHODS:Breast cancer cell lines (BT-20, BT-474, MDA-MB-231, MDA-MB-436, MDA-MB-453, MCF-7, SKBR3, T47D, ZR-75-1) and the mammary epithelial cell line MCF-10A were treated with TRAIL and ATRA alone and in combination. Cell viability was assessed via 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide (MTT) assay, the potential of cell colony formation via clonogenic assay, cell death induction via cell-cycle analysis by fluorescence-activated cell sorting (FACS), terminal deoxynucleotidyltransferase-mediated UTP nick end labeling (TUNEL) assay and Cell death detection ELISA, expression of apoptosis and TRAIL pathway proteins via western blot and cell surface expression of TRAIL receptor 1 (DR4) via FACS analysis. RESULTS:TRAIL and ATRA evoked synergistic inhibition of breast cancer cell viability based on cytostatic and cytotoxic mechanisms. This correlated with augmented fragmentation of nuclear DNA, up-regulation of TRAIL receptor, down-regulation of cyclin D1 and enhancement of caspase activity. MCF-10A cells were merely slightly susceptible to TRAIL and ATRA. CONCLUSION:The cytostatic and cytotoxic effects of the combination of TRAIL and ATRA are tumor cell-selective.
10.21873/anticanres.12509
Targeting TRAIL Death Receptors in Triple-Negative Breast Cancers: Challenges and Strategies for Cancer Therapy.
Cells
The tumor necrosis factor (TNF) superfamily member TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells via death receptor (DR) activation with little toxicity to normal cells or tissues. The selectivity for activating apoptosis in cancer cells confers an ideal therapeutic characteristic to TRAIL, which has led to the development and clinical testing of many DR agonists. However, TRAIL/DR targeting therapies have been widely ineffective in clinical trials of various malignancies for reasons that remain poorly understood. Triple negative breast cancer (TNBC) has the worst prognosis among breast cancers. Targeting the TRAIL DR pathway has shown notable efficacy in a subset of TNBC in preclinical models but again has not shown appreciable activity in clinical trials. In this review, we will discuss the signaling components and mechanisms governing TRAIL pathway activation and clinical trial findings discussed with a focus on TNBC. Challenges and potential solutions for using DR agonists in the clinic are also discussed, including consideration of the pharmacokinetic and pharmacodynamic properties of DR agonists, patient selection by predictive biomarkers, and potential combination therapies. Moreover, recent findings on the impact of TRAIL treatment on the immune response, as well as novel strategies to address those challenges, are discussed.
10.3390/cells11233717
TRAIL Mediated Signaling in Breast Cancer: Awakening Guardian Angel to Induce Apoptosis and Overcome Drug Resistance.
Yin Ning,Yi Liu,Khalid Sumbul,Ozbey Ulku,Sabitaliyevich Uteuliev Yerzhan,Farooqi Ammad Ahmad
Advances in experimental medicine and biology
Sequencing technologies have allowed us to characterize highly heterogeneous molecular landscape of breast cancer with unprecedented details. Tremendous breakthroughs have been made in unraveling contributory role of signaling pathways in breast cancer development and progression. It is becoming progressively more understandable that deregulation of spatio-temporally controlled pathways underlie development of resistance against different drugs. TRAIL mediated signaling has attracted considerable appreciation because of its characteristically unique ability to target cancer cells while leaving normal cells intact. Discovery of TRAIL was considered as a paradigm shift in molecular oncology because of its conspicuous ability to selectively target cancer cells. There was an exponential growth in the number of high-quality reports which highlighted cancer targeting ability of TRAIL and scientists worked on the development of TRAIL-based therapeutics and death receptor targeting agonistic antibodies to treat cancer. However, later studies challenged simplistic view related to tumor targeting ability of TRAIL. Detailed mechanistic insights revealed that overexpression of anti-apoptotic proteins, inactivation of pro-apoptotic proteins and downregulation of death receptors were instrumental in impairing apoptosis in cancer cells. Therefore researchers started to give attention to identification of methodologies and strategies to overcome the stumbling blocks associated with TRAIL-based therapeutics. Subsequent studies gave us a clear picture of signaling cascade of TRAIL and how deregulation of different proteins abrogated apoptosis. In this chapter we have attempted to provide an overview of the TRAIL induced signaling, list of proteins frequently deregulated and modern approaches to strategically restore apoptosis in TRAIL-resistant breast cancers.
10.1007/978-3-030-20301-6_12
Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding.
Science advances
Endothelial cells (ECs) grant access of disseminated cancer cells to distant organs. However, the molecular players regulating the activation of quiescent ECs at the premetastatic niche (PMN) remain elusive. Here, we find that ECs at the PMN coexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate death receptor 5 (DR5). Unexpectedly, endothelial TRAIL interacts intracellularly with DR5 to prevent its signaling and preserve a quiescent vascular phenotype. In absence of endothelial TRAIL, DR5 activation induces EC death and nuclear factor κB/p38-dependent EC stickiness, compromising vascular integrity and promoting myeloid cell infiltration, breast cancer cell adhesion, and metastasis. Consistently, both down-regulation of endothelial TRAIL at the PMN by proangiogenic tumor-secreted factors and the presence of the endogenous TRAIL inhibitors decoy receptor 1 (DcR1) and DcR2 favor metastasis. This study discloses an intracrine mechanism whereby TRAIL blocks DR5 signaling in quiescent endothelia, acting as gatekeeper of the vascular barrier that is corrupted by the tumor during cancer cell dissemination.
10.1126/sciadv.add5028