scholarly journals Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

2021 ◽  
Vol 12 ◽  
Author(s):  
Ehsan Razeghian ◽  
Wanich Suksatan ◽  
Heshu Sulaiman Rahman ◽  
Dmitry O. Bokov ◽  
Walid Kamal Abdelbasset ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Tumor Cells ◽  
Combined Treatment ◽  
Death Receptor ◽  
Human Mscs ◽  
Regulation Of Expression ◽  
Apoptosis Pathway ◽  
Trail Resistance ◽  
Apoptotic Proteins

The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted rapidly evolving attention as a cancer treatment modality because of its competence to selectively eliminate tumor cells without instigating toxicity in vivo. TRAIL has revealed encouraging promise in preclinical reports in animal models as a cancer treatment option; however, the foremost constraint of the TRAIL therapy is the advancement of TRAIL resistance through a myriad of mechanisms in tumor cells. Investigations have documented that improvement of the expression of anti-apoptotic proteins and survival or proliferation involved signaling pathways concurrently suppressing the expression of pro-apoptotic proteins along with down-regulation of expression of TRAILR1 and TRAILR2, also known as death receptor 4 and 5 (DR4/5) are reliable for tumor cells resistance to TRAIL. Therefore, it seems that the development of a therapeutic approach for overcoming TRAIL resistance is of paramount importance. Studies currently have shown that combined treatment with anti-tumor agents, ranging from synthetic agents to natural products, and TRAIL could result in induction of apoptosis in TRAIL-resistant cells. Also, human mesenchymal stem/stromal cells (MSCs) engineered to generate and deliver TRAIL can provide both targeted and continued delivery of this apoptosis-inducing cytokine. Similarly, nanoparticle (NPs)-based TRAIL delivery offers novel platforms to defeat barricades to TRAIL therapeutic delivery. In the current review, we will focus on underlying mechanisms contributed to inducing resistance to TRAIL in tumor cells, and also discuss recent findings concerning the therapeutic efficacy of combined treatment of TRAIL with other antitumor compounds, and also TRAIL-delivery using human MSCs and NPs to overcome tumor cells resistance to TRAIL.

scholarly journals Lambertianic Acid Sensitizes Non-Small Cell Lung Cancers to TRAIL-Induced Apoptosis Via Inhibition of XIAP/NF-kB and Activation of Caspases and Death Receptor 4

2018 ◽  
Author(s):  
Deoksoo Ahn ◽  
HyoJung Lee ◽  
Jisung Hwang ◽  
Hyukgyu Han ◽  
BumSang Shim ◽  
...  
Keyword(s):  
Combined Treatment ◽  
Death Receptor ◽  
B Cell Lymphoma ◽  
Small Cell ◽  
Pinus Koraiensis ◽  
Small Cell Lung ◽  
Lambertianic Acid ◽  
Apoptotic Proteins ◽  
Induced Apoptosis ◽  
Death Receptor 4

Lambertianic acid (LA) is a biologically active compound from the leaves of Pinus koraiensis. In the present study, apoptotic mechanisms of LA plus TNF-related apoptosis-inducing ligand (TRAIL) were elucidated in non-small cell lung cancer cells (NSCLCs). Cytotoxicity assay, flow cytometry, immunoprecipitation and Western blotting were performed. Here, combined treatment of LA and TRAIL increased cytotoxicity, sub-G1 population and cleaved poly (ADP-ribose) polymerase (PARP) and caspase3/8/9 in A549 and H1299 cells compared to LA or TRAIL alone. Furthermore, combined treatment of LA and TRAIL significantly decreased anti-apoptotic proteins such as B-cell lymphoma 2 (Bcl-2), Fas-like inhibitor protein (FLIP) and X-linked inhibitor of apoptosis protein (XIAP) and enhanced the activation of pro-apoptotic proteins Bid compared to LA or TRAIL alone. In addition, combined treatment of LA and TRAIL upregulated the expression of Death receptor 4 (DR4) and downregulated phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-B), inhibitory protein of kB family (p-IB) and FLIP in A549 and H1299 cells along with disrupted binding of XIAP with caspase3 or NF-B. Overall, these findings suggest that lambertianic acid enhances TRAIL-induced apoptosis via inhibition of XIAP/NF-B in TRAIL resistant NSCLCs.

scholarly journals Dexamethasone enhances the lung metastasis of breast cancer via a PI3K-SGK1-CTGF pathway

Oncogene ◽  
2021 ◽  
Author(s):  
Yujing Zhang ◽  
Gang Shi ◽  
Hantao Zhang ◽  
Qi Xiong ◽  
Fuyi Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Tumor Cells ◽  
Breast Cancer Cell ◽  
Lung Metastasis ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Treatment

AbstractDexamethasone (Dex), as a pretreatment agent, is widely used to attenuate the side effects of chemotherapy in breast cancer treatment. However, whether and how Dex affects breast cancer metastasis remain to be furtherly understood. In this study, we established several mouse breast cancer metastatic models to study the effect of Dex in vitro and in vivo. Transwell, Western Blot and RNA interference were applied to study the molecular mechanism of Dex in promoting breast cancer cell migration. Meanwhile, the effect of Dex on lung metastasis of breast cancer in Dex combined with PTX chemotherapy was discussed. Our results confirmed that Dex could promote breast cancer cell metastasis both in vitro and in vivo. Mechanistic studies revealed that this pro-metastatic effect of Dex was mediated by the GR-PI3K-SGK1-CTGF pathway in tumor cells. Ligation of Dex and glucocorticoid receptor (GR) on tumor cells activated the PI3K signaling pathway and upregulated serum glucocorticoid-inducible kinase 1 (SGK1) expression, and then increased the expression of connective tissue growth factor (CTGF) through Nedd4l-Smad2. Moreover, Dex was the leading factor for lung metastasis in a standard regimen for breast cancer treatment with paclitaxel and Dex. Importantly, targeting SGK1 with the inhibitor GSK650394 remarkably reduced lung metastasis in this regimen. Our present data provide new insights into Dex-induced breast cancer metastasis and indicate that SGK1 could be a candidate target for the treatment of breast cancer metastasis.

scholarly journals Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD

2005 ◽  
Vol 390 (3) ◽  
pp. 729-735 ◽  
Author(s):  
Hemamalini Renganathan ◽  
Hema Vaidyanathan ◽  
Anna Knapinska ◽  
Joe W. Ramos
Keyword(s):  
Protein Kinase ◽  
Cell Signalling ◽  
Death Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Death Domain ◽  
Apoptosis Pathway ◽  
Akt Phosphorylation ◽  
Erk Mapk

Cell signalling pathways that regulate proliferation and those that regulate programmed cell death (apoptosis) are co-ordinated. The proteins and mechanisms that mediate the integration of these pathways are not yet fully described. The phosphoprotein PEA-15 (phosphoprotein enriched in astrocytes) can regulate both the ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) pathway and the death receptor-initiated apoptosis pathway. This is the result of PEA-15 binding to the ERK/MAPK or the proapoptotic protein FADD (Fas-activated death domain protein) respectively. The mechanism by which binding of PEA-15 to these proteins is controlled has not been elucidated. PEA-15 is a phosphoprotein containing a Ser-104 phosphorylated by protein kinase C and a Ser-116 phosphorylated by CamKII (calcium/calmodulin-dependent protein kinase II) or AKT. Phosphorylation of Ser-104 is implicated in the regulation of glucose metabolism, while phosphorylation at Ser-116 is required for PEA-15 recruitment to the DISC (death-initiation signalling complex). Moreover, PEA-15 must be phosphorylated at Ser-116 to inhibit apoptosis. In the present study, we report that phosphorylation at Ser-104 blocks ERK binding to PEA-15 in vitro and in vivo, whereas phosphorylation at Ser-116 promotes its binding to FADD. We further characterize phospho-epitope-binding antibodies to these sites. We report that phosphorylation does not influence the distribution of PEA-15 between the cytoplasm and nucleus of the cell since all phosphorylated states are found predominantly in the cytoplasm. We propose that phosphorylation of PEA-15 acts as the switch that controls whether PEA-15 influences proliferation or apoptosis.

scholarly journals Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma

2010 ◽  
Vol 188 (6) ◽  
pp. 851-862 ◽  
Author(s):  
Bernhard Gillissen ◽  
Jana Wendt ◽  
Antje Richter ◽  
Anja Richter ◽  
Annika Müer ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Death Receptor ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

Tumor necrosis factor (α)–related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that preferentially kills tumor cells with limited cytotoxicity to nonmalignant cells. However, signaling from death receptors requires amplification via the mitochondrial apoptosis pathway (type II) in the majority of tumor cells. Thus, TRAIL-induced cell death entirely depends on the proapoptotic Bcl-2 family member Bax, which is often lost as a result of epigenetic inactivation or mutations. Consequently, Bax deficiency confers resistance against TRAIL-induced apoptosis. Despite expression of Bak, Bax-deficient cells are resistant to TRAIL-induced apoptosis. In this study, we show that the Bax dependency of TRAIL-induced apoptosis is determined by Mcl-1 but not Bcl-xL. Both are antiapoptotic Bcl-2 family proteins that keep Bak in check. Nevertheless, knockdown of Mcl-1 but not Bcl-xL overcame resistance to TRAIL, CD95/FasL and tumor necrosis factor (α) death receptor ligation in Bax-deficient cells, and enabled TRAIL to activate Bak, indicating that Mcl-1 rather than Bcl-xL is a major target for sensitization of Bax-deficient tumors for death receptor–induced apoptosis via the Bak pathway.

The Role of VEGFA in Malignant Progression in AML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 203-203 ◽  
Author(s):  
Alida C Weidenaar ◽  
Arja ter Elst ◽  
Henk-Marijn de Jonge ◽  
Tiny Meeuwsen-de Boer ◽  
Willem A Kamps ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathways ◽  
Tumor Cells ◽  
Critical Role ◽  
Malignant Progression ◽  
Endothelial Cell Proliferation ◽  
Receptor Interaction ◽  
Apoptosis Pathway

Abstract Vascular Endothelial Growth Factor (VEGFA) at time of diagnosis is an independent prognostic factor for poor treatment outcome in (pediatric) acute myeloid leukemia (AML). Inhibition of VEGFA by Bevacizumab, a recombinant humanized monoclonal antibody, preceded by chemotherapy yields a favorable CR rate and duration in adults with refractory AML (Karp et al., 2004). VEGFA is a powerful stimulator of angiogenesis; VEGFA binds to the tyrosine kinase receptors VEGFR1 and VEGFR2 on endothelial cells, resulting in endothelial cell proliferation. Moreover, binding of VEGFA to VEGF receptors on AML cells in vitro promotes leukemic cell survival via activation of signaling pathways such as RAS/Raf/MEK/ERK and PI3K/AKT pathway. In our study a model was generated to investigate the effect of VEGFA in malignant progression in AML. An HL-60 AML cell line was transduced with VEGFA (the splice variant VEGFA165) or a control vector using a retroviral construct. With RT-PCR we found a threefold induction of VEGFA in VEGFA165 transduced cells. No difference in growth rate and drug sensitivity was found between the HL-60 VEGFA165 cells and HL-60 control cells in vitro. Thus, VEGFA165 overexpression did not result in growth benefit in vitro. To evaluate the in vivo effects of VEGFA165 overexpression, we injected 10 × 106 HL-60 VEGFA165 cells or HL-60 control cells s.c. into NOD/SCID mice (n=14). We observed that overexpression of VEGFA165 increased tumor weight (median weight: HL-60 VEGFA165 tumors 995 mg, range 670–1344; HL-60 control tumors 464 mg, range 413–646; p=0.001). So, the effects of AML overexpressed VEGFA165 are detectable in combination with its environment. Using gene expression profiles (Affymetrix) we found differentially activated signaling pathways, e.g. the PI3K/AKT (p<0.001), MAPK (p<0.001), Jak-STAT (p<0.001) and VEGF-pathway (p<0.001), as well as pathways involved in cell interaction. With GeneTrail (a web-based application that scores a sorted list of genes with respect to their enrichment of functional categories) and the transcriptional system regulator approach (De Jonge et al., 2008) we could demonstrate that the Jak-STAT pathway (p=0.02) as well as the apoptosis pathway (p=0.04) was more active in the VEGFA165 HL-60 tumors, whereas the cytokine-cytokine receptor interaction was more active in de HL-60 control tumors (p=0.02). In addition, we found differential expression of the process angiogenesis (p=0.002). Cell proliferation within the tumors was verified by staining for Ki67; the HL-60 VEGFA165 tumor cells showed more proliferation than the HL-60 control tumor cells, as a netto result of multiple signaling pathway activation (p=0.02). In conclusion, overexpression of VEGFA165 did not have a growth benefit in vitro, whereas in vivo an increase in tumor volume was seen when VEGFA165 was overexpressed. VEGFA related pro-angiogenic effects are found in the AML tumor cells as well as enhanced signaling and proliferation in AML tumor cells in vivo. Therefore, the interaction of VEGFA165 with its environment plays a critical role in the malignant progression in AML. New design drugs related to VEGF/VEGFR interaction need to be tested in context of a tumor in its environment.

scholarly journals Black phosphorus nanosheets and paclitaxel encapsulated hydrogel for synergistic photothermal-chemotherapy

Nanophotonics ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shoushan Sang ◽  
Zhipeng Jiang ◽  
Ning Xie ◽  
Huaxin Rao ◽  
Kedan Liao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Treatment ◽  
Tumor Cells ◽  
Black Phosphorus ◽  
Photothermal Effect ◽  
Tumor Treatment ◽  
Gastric Cancer Cells ◽  
Tumor Cell Apoptosis ◽  
Gastric Cancer Treatment

Abstract Gastric cancer treatment remains a major challenge because of its aggressiveness and spread. In this study, we developed a hydrogel system for the treatment of gastric cancer, which can kill tumor cells through photothermal action and drug treatment. Based on the formation of Schiff base linkage, the OSA/AHA/BP/PTX hydrogel was prepared by mixing oxidized sodium alginate (OSA), aminated hyaluronic acid (AHA), black phosphorus (BP), and paclitaxel (PTX) under physiological conditions, which exhibited excellent photothermal effect and slow release ability PTX. Moreover, CCK-8 and live/dead fluorescent confirmed that OSA/AHA/BP/PTX hydrogel could obvious inhibition the proliferation of gastric cancer cells (SGC7901). More importantly, in vivo experiments further show that the prepared hydrogel can significantly improve the tumor treatment effect of tumor-bearing mice by inducing tumor cell apoptosis and inhibiting the proliferation of new tumor cells. Compared with chemotherapy alone, photothermal combined chemotherapy had a better antitumor effect. The results of this study indicate that the composite hydrogel with controlled release of paclitaxel can be used as a candidate material for cancer treatment.

Generation of tumor-specific cytotoxic T lymphocytes in vivo by combined treatment with inactivated tumor cells and recombinant interleukin-2

1994 ◽  
Vol 38 (5) ◽  
pp. 332-338 ◽  
Author(s):  
Mamoru Harada ◽  
Goro Matsuzaki ◽  
Yoshihiro Shinomiya ◽  
Shin Kurosawa ◽  
Osamu Ito ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Tumor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Combined Treatment ◽  
Interleukin 2 ◽  
Recombinant Interleukin 2

scholarly journals NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1830 ◽  
Author(s):  
Tung-Yung Huang ◽  
Tung-Cheng Chang ◽  
Yu-Tang Chin ◽  
Yi-Shin Pan ◽  
Wong-Jin Chang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Combined Treatment ◽  
Proliferative Effect ◽  
Pi3k Activation

The property of drug-resistance may attenuate clinical therapy in cancer cells, such as chemoresistance to gefitinib in colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and metastasis in cancer cells; therefore, the PD-L1 pathway allows tumor cells to exert an adaptive resistance mechanism in vivo. Nano-diamino-tetrac (NDAT) has been shown to enhance the anti-proliferative effect induced by first-line chemotherapy in various types of cancer, including colorectal cancer (CRC). In this work, we attempted to explore whether NDAT could enhance the anti-proliferative effect of gefitinib in CRC and clarified the mechanism of their interaction. The MTT assay was utilized to detect a reduction in cell proliferation in four primary culture tumor cells treated with gefitinib or NDAT. The gene expression of PD-L1 and other tumor growth-related molecules were quantified by quantitative polymerase chain reaction (qPCR). Furthermore, the identification of PI3K and PD-L1 in treated CRC cells were detected by western blotting analysis. PD-L1 presentation in HCT116 xenograft tumors was characterized by specialized immunohistochemistry (IHC) and the hematoxylin and eosin stain (H&E stain). The correlations between the change in PD-L1 expression and tumorigenic characteristics were also analyzed. (3) The PD-L1 was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, the PD-L1 expression was decreased by gefitinib (1 µM and 10 µM) in two cells (Colo_150624 and 160426), but 10 µM gefitinib stimulated PD-L1 expression in gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reduced PD-L1 expression and proliferation in CRC Colo_160224 cells. Gefitinib didn’t inhibit PD-L1 expression and PI3K activation in gefitinib-resistant Colo_160224 cells. However, NDAT inhibited PI3K activation as well as PD-L1 accumulation in gefitinib-resistant Colo_160224 cells. The combined treatment of NDAT and gefitinib inhibited pPI3K and PD-L1 expression and cell proliferation. Additionally, NDAT reduced PD-L1 accumulation and tumor growth in the HCT116 (K-RAS mutant) xenograft experiment. (4) Gefitinib might suppress PD-L1 expression but did not inhibit proliferation through PI3K in gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in gefitinib-resistant CRCs.

scholarly journals Combination of Mesenchymal Stem Cell-Delivered Oncolytic Virus with Prodrug Activation Increases Efficacy and Safety of Colorectal Cancer Therapy

2020 ◽  
Author(s):  
Chun-Te Ho ◽  
Mei-Hsuan Wu ◽  
Ming-Jen Chen ◽  
Shih-Pei Lin ◽  
Shih-Chieh Hung
Keyword(s):  
Cancer Treatment ◽  
Tumor Cells ◽  
Trichostatin A ◽  
Oncolytic Viruses ◽  
Tumor Growth Inhibition ◽  
Adenoviral Infection ◽  
Viral Therapy ◽  
Tumor Tropism

Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. Methods: MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Results: Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-Adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. Conclusion: This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.

scholarly journals Overcoming TRAIL Resistance for Glioblastoma Treatment

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 572
Author(s):  
Longfei Deng ◽  
Xuan Zhai ◽  
Ping Liang ◽  
Hongjuan Cui
Keyword(s):  
Therapeutic Potential ◽  
Death Receptor ◽  
Apoptosis Pathway ◽  
Reasonable Expectation ◽  
The Status ◽  
Extrinsic Apoptosis ◽  
Trail Resistance ◽  
Induced Apoptosis ◽  
Trail Death Receptor ◽  
Necrosis Factor

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows a promising therapeutic potential in cancer treatment as it exclusively causes apoptosis in a broad spectrum of cancer cells through triggering the extrinsic apoptosis pathway via binding to cognate death receptors, with negligible toxicity in normal cells. However, most cancers, including glioblastoma multiforme (GBM), display TRAIL resistance, hindering its application in clinical practice. Recent studies have unraveled novel mechanisms in regulating TRAIL-induced apoptosis in GBM and sought effective combinatorial modalities to sensitize GBM to TRAIL treatment, establishing pre-clinical foundations and the reasonable expectation that the TRAIL/TRAIL death receptor axis could be harnessed to treat GBM. In this review, we will revisit the status quo of the mechanisms of TRAIL resistance and emerging strategies for sensitizing GBM to TRAIL-induced apoptosis and also discuss opportunities of TRAIL-based combinatorial therapies in future clinical use for GBM treatment.

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