Chemotherapeutic Agents Sensitize Resistant Cancer Cells to the DR5-Specific Variant DR5-B More Efficiently Than to TRAIL by Modulating the Surface Expression of Death and Decoy Receptors

Artykov, Artem A.; Belov, Dmitry; Shipunova, Victoria O.; Trushina, Daria B.; Deyev, Sergey M.; Долгих, Д. А.; Kirpichnikov, Mikhaǐl P.; Gasparian, Marine E.

doi:10.3390/cancers12051129

Cited by 10 publications

(10 citation statements)

References 46 publications

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“…It was demonstrated that the DISC formed by DR5-B did not contain DR4 receptor in the HT-29 and PANC-1 cell lines, while in the DISC formed by TRAIL both DRs were detected. However, DR4 internalization by DR5-B was observed earlier after strong upregulation of the surface DRs by chemotherapeutic agents ( Artykov et al, 2020 ). Obviously, increased expression of death receptors on the cell surface promotes the formation of heterodimers where the receptors can be internalized together as part of the same DISC ( Szegezdi et al, 2012 ).…”

Section: Resultsmentioning

confidence: 99%

Death Receptors DR4 and DR5 Undergo Spontaneous and Ligand-Mediated Endocytosis and Recycling Regardless of the Sensitivity of Cancer Cells to TRAIL

Artykov

Yagolovich

Долгих

et al. 2021

Front. Cell Dev. Biol.

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Tumor necrosis factor-associated ligand inducing apoptosis (TRAIL) induces apoptosis through the death receptors (DRs) 4 and 5 expressed on the cell surface. Upon ligand stimulation, death receptors are rapidly internalized through clathrin-dependent and -independent mechanisms. However, there have been conflicting data on the role of death receptor endocytosis in apoptotic TRAIL signaling and possible cell type-specific differences in TRAIL signaling have been proposed. Here we have compared the kinetics of TRAIL-mediated internalization and subsequent recycling of DR4 and DR5 in resistant (HT-29 and A549) and sensitive (HCT116 and Jurkat) tumor cell lines of various origin. TRAIL stimulated the internalization of both receptors in a concentration-dependent manner with similar kinetics in sensitive and resistant cell lines without affecting the steady-state expression of DR4 and DR5 in cell lysates. Using the receptor-selective TRAIL variant DR5-B, we have shown that DR5 is internalized independently of DR4 receptor. After internalization and elimination of TRAIL from culture medium, the receptors slowly return to the plasma membrane. Within 4 h in resistant or 6 h in sensitive cells, the surface expression of receptors was completely restored. Recovery of receptors occurred both from newly synthesized molecules or from trans-Golgi network, as cycloheximide and brefeldin A inhibited this process. These agents also suppressed the expression of cell surface receptors in a time- and concentration-dependent manner, indicating that DRs undergo constitutive endocytosis. Inhibition of receptor endocytosis by sucrose led to sensitization of resistant cells to TRAIL and to an increase in its cytotoxic activity against sensitive cells. Our results confirm the universal nature of TRAIL-induced death receptor endocytosis, thus cell sensitivity to TRAIL can be associated with post-endocytic events.

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Section: Resultsmentioning

confidence: 99%

Death Receptors DR4 and DR5 Undergo Spontaneous and Ligand-Mediated Endocytosis and Recycling Regardless of the Sensitivity of Cancer Cells to TRAIL

Artykov

Yagolovich

Долгих

et al. 2021

Front. Cell Dev. Biol.

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“…The selectivity of the cancer cells to TIC10 and TRAIL-inducing compounds relies on the overexpression of DR4 and DR5 compared to non-cancerous cells [ 37 , 38 ]; thus, these compounds are promising targeted drugs. In earlier studies, it was reported that BOZ could enhance the expression of these death receptors (DR4 and DR5) [ 20 , 21 , 39 ]. As it was proposed, our results confirm these previous findings as increased surface receptor expression of DR5 was detected after BOZ and BOZ+TIC10 treatments in the investigated A2058 melanoma cell line.…”

Section: Discussionmentioning

confidence: 99%

“…In the literature, it was demonstrated that BOZ could enhance the expression of proteins, e.g., DR4 or DR5, in HT-29 human colorectal adenocarcinoma cells, in A549 human lung adenocarcinoma cells and in human non-small cell lung cancer cells [ 20 , 21 ]. We hypothesized that following a co-treatment with BOZ and TIC10, the enhancement in the expression of the TRAIL protein post-TIC10 treatment and the upregulation of the death receptors post-BOZ treatment could lead to reduced cell viability.…”

Section: Introductionmentioning

confidence: 99%

The Synergistic Activity of Bortezomib and TIC10 against A2058 Melanoma Cells

et al. 2021

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Combination antitumor treatments are essential parts of modern tumor therapy as—compared to monotherapies—(i) they are more effective; (ii) the dose of the compounds can be reduced; and (iii) therefore the side effects are improved. Our research group previously demonstrated the antitumor character of bortezomib (BOZ) in A2058 melanoma cells. Unfortunately, dose-related side effects are common during BOZ therapy, which could be prevented by reducing the dose of BOZ. This study aimed to characterize synergistic combinations of BOZ with a TRAIL (TNF-related apoptosis-inducing ligand) -inducing compound (TIC10), where the doses can be cut down but the efficacy is preserved. Endpoint cell viability assays were performed on A2058 cells, and synergism of BOZ and TIC10 was observed after 72 h. Synergism was further validated in a real-time impedimetric assay, and our results showed that BOZ-treated melanoma cells survived the treatment, an effect not registered in the co-treatments. Treatment with the combinations resulted in increased apoptosis, which was not accompanied by enhanced LDH release. Nevertheless, the expression of death receptor 5 (DR5) was increased on the cell surface without transcriptional regulation. In summary, our findings support the theory that the application of BOZ and TIC10 in combination could provide higher efficacy in vitro.

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“…Several studies have reported the anti-tumor activity of MSC-TRAIL against lung cancer, specifically in pre-clinical models of NSCLC [ 48 , 49 , 50 ]. However, the characteristic of TRAIL resistance has been observed in some of the NSCLC cell lines, indicating that not all the NSCLC subtypes would benefit from MSC-TRAIL treatment [ 51 , 52 ]. In this study, we have shown for the first time that chemo-sensitization of the NSCLC cell lines and their CSCs, particularly the CD133+ population, using first-line chemotherapies such as cisplatin, 5-FU and vinorelbine was able to enhance the anti-tumor effect of MSC-TRAIL.…”

Section: Discussionmentioning

confidence: 99%

Chemo-Sensitization of CD133+ Cancer Stem Cell Enhances the Effect of Mesenchymal Stem Cell Expressing TRAIL in Non-Small Cell Lung Cancer Cell Lines

Fakiruddin

Lim

Nordin

et al. 2021

Biology

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Pre-clinical studies have demonstrated the efficacy of mesenchymal stem cells (MSCs) expressing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or MSC-TRAIL against several tumors. However, due to the existence of cancer stem cells (CSCs), some tumors, including non-small cell lung cancer (NSCLC), exhibit TRAIL resistance. This study was designed to evaluate the capacity of using first-line chemotherapies including cisplatin, 5-fluorouracil (5-FU) and vinorelbine to act as a chemo-sensitizer on CD133+ (prominin-1 positive) CSCs derived from NSCLC cell lines (A549, H460 and H2170) for the purpose of MSC-TRAIL-induced inhibition. We showed that MSC-TRAIL was resistant to all three chemotherapies compared to the NSCLC cell lines, suggesting that the chemotherapies had little effect on MSC-TRAIL viability. Pre-treatment using either cisplatin or 5-FU, but not with vinorelbine, was able to increase the efficacy of MSC-TRAIL to kill the TRAIL-resistant A549-derived CSCs. The study also demonstrated that both 5-FU and vinorelbine were an effective chemo-sensitizer, used to increase the anti-tumor effect of MSC-TRAIL against H460- and H2170-derived CSCs. Furthermore, pre-treatment using cisplatin was noted to enhance the effect of MSC-TRAIL in H460-derived CSCs; however, this effect was not detected in the H2170-derived CSCs. These findings suggest that a pre-treatment using certain chemotherapies in NSCLC could enhance the anti-tumor effect of MSC-TRAIL to target the CSCs, and therefore the combination of chemotherapies and MSC-TRAIL may serve as a novel approach for the treatment of NSCLC.

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Chemotherapeutic Agents Sensitize Resistant Cancer Cells to the DR5-Specific Variant DR5-B More Efficiently Than to TRAIL by Modulating the Surface Expression of Death and Decoy Receptors

Cited by 10 publications

References 46 publications

Death Receptors DR4 and DR5 Undergo Spontaneous and Ligand-Mediated Endocytosis and Recycling Regardless of the Sensitivity of Cancer Cells to TRAIL

Death Receptors DR4 and DR5 Undergo Spontaneous and Ligand-Mediated Endocytosis and Recycling Regardless of the Sensitivity of Cancer Cells to TRAIL

The Synergistic Activity of Bortezomib and TIC10 against A2058 Melanoma Cells

Chemo-Sensitization of CD133+ Cancer Stem Cell Enhances the Effect of Mesenchymal Stem Cell Expressing TRAIL in Non-Small Cell Lung Cancer Cell Lines

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