Duloxetine Enhances TRAIL-mediated Apoptosis <i>via</i> AMPK-mediated Inhibition of Autophagy Flux in Lung Cancer Cells

Zinnah, Kazi Md. Ali; Park, Sang-Youel

doi:10.21873/anticanres.13877

Cited by 16 publications

(7 citation statements)

References 54 publications

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“…The levels of LDH secretion detected in the groups treated with TRAIL and MIX indicated that TRAIL induced apoptosis significantly. These results were also observed in lung cancer cells (lines A549, HCC-15) in which there was a greater release of LDH in the groups treated with TRAIL, showing that there was induction of apoptosis by this protein [56]. The same pattern was demonstrated in another study with 2 isoforms of TRAIL in the treatment against 3 human bladder cancer strains [57].…”

Section: Discussionsupporting

confidence: 73%

Antitumor Effect of IL-2 and TRAIL Proteins Expressed by Recombinant Salmonella in Murine Bladder Cancer Cells

Fragelli

Camillo

Rodolpho

et al. 2021

Cell Physiol Biochem

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Background/Aims: Cancer is the second most deadly disease in the world. The bladder cancer is one of the most aggressive types and shows a continuous increase in the number of cases. The use of bacteria as live vectors to deliver molecules directly to the tumor is a promising tool and has been used as an adjuvant treatment against several types of cancer. The aim of this study was to investigate the antitumor effect of Interleukin 2 (IL-2), TNF-related apoptosis-inducing ligand (TRAIL) and protein MIX against murine bladder cancer cells, lineage MB49. Methods: The attenuated Salmonella strain SL3261 was transformed by inserting the IL-2 and TRAIL genes. The effects of proteins on cell viability (MTT method), cell morphology (optical microscopy), cell recovery (clonogenic assay), cell membrane (lactate dehydrogenase release - LDH), on oxidative stress pathway (levels of nitric oxide, NO) and apoptosis (flow cytometry and high resolution epifluorescence images) were evaluated at intervals of 24 and 48 hours of action. Results: The results showed that there was a decrease in cell viability via damage to the cell membrane, alteration of cell morphology, non-recovery of cells, increase in the production of NO and incubate for of cells in the state of apoptosis in the two periods analyzed. Conclusion: The data presented suggest that IL-2, TRAIL and their MIX proteins in MB49 cells have cytotoxic potential and that this is associated with oxidative stress and apoptosis pathways. These results may contribute to the development of new therapeutic strategies for bladder cancer.

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Section: Discussionsupporting

confidence: 73%

Antitumor Effect of IL-2 and TRAIL Proteins Expressed by Recombinant Salmonella in Murine Bladder Cancer Cells

Fragelli

Camillo

Rodolpho

et al. 2021

Cell Physiol Biochem

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“…LC3-II is a well-known marker indicating the formation of a complete autophagosome, while p62 is involved in the lysosome-and proteasome-dependent degradation of proteins. Inhibition of autophagy results in the accumulation of cellular p62 (51). The findings of the present study suggested that sertraline increases the number of autophagosomes, as evident from the enlarged volume of Lc3-II, and triggers the degradation of lysosomes, consistent with the accumulation of p62.…”

Section: Discussionsupporting

confidence: 69%

Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation

2020

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential target for cancer therapy, owing to its ability to selectively kill cancer cells without causing significant toxicity to normal cells. However, due to the lack of death receptor expression, cancer cells can become highly resistant to TRAIL. Hence, it is vital to develop agents that restore TRAIL efficacy. Sertraline is an antidepressant drug with anticancer properties. To the best of our knowledge, this is the first study to demonstrate that sertraline inhibits autophagic flux and increases the expression of death receptor 5 (DR5) on TRAIL-resistant lung cancer cells. Inhibition of autophagy using autophagy inhibitors 3-methyladenine and chloroquine upregulated the expression of DR5 and enhanced TRAIL-induced apoptosis, as confirmed by the increase of pro-apoptotic proteins caspase-8 and caspase-3. Silencing DR5 expression using DR5 small interfering RNA prevented sertraline-induced TRAIL-mediated apoptosis, indicating the role of DR5 in TRAIL-mediated apoptosis. Overall, sertraline enhanced TRAIL-mediated apoptosis via the downregulation of AMP-activated protein kinase phosphorylation, resulting in the inhibition of autophagic flux, upregulation of DR5 expression, and activation of the apoptotic caspase cascade. These data suggested that sertraline could be used to sensitize human lung cancer cells to TRAIL, while also serving as a therapeutic option in cancer patients with depression.

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“…Since HDACs are associated with changes in glycosylation patterns, O-glycosylation, N-glycosylation, and fucosylation in DR4 and DR5 receptors are necessary to improve TRAIL signaling. Thus, HDAC inhibitors have been proposed as another strategy against cancer since they maintain glycosylation in TRAIL receptors [ 107 ]. In addition, HDAC inhibitors act in synergy with TRAIL by upregulating the mitochondrial pathway; downregulating NF-kβ and its gene products, such as cyclin D1, Bcl-2, Bcl-XL, VEGF, HIF-1a, IL6, IL8, MMP-2, and MMP-9; and upregulating the pro-apoptotic proteins Bax, Bak, and p21/CIP1 and TRAIL receptors DR4 and DR5 in cancer cells [ 108 ].…”

Section: Mechanism Against Trail Resistancementioning

confidence: 99%

Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL

Quiroz-Reyes,

Delgado-Gonzalez,

Islas

et al. 2021

Pharmaceutics

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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.

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Duloxetine Enhances TRAIL-mediated Apoptosis via AMPK-mediated Inhibition of Autophagy Flux in Lung Cancer Cells

Cited by 16 publications

References 54 publications

Antitumor Effect of IL-2 and TRAIL Proteins Expressed by Recombinant Salmonella in Murine Bladder Cancer Cells

Antitumor Effect of IL-2 and TRAIL Proteins Expressed by Recombinant Salmonella in Murine Bladder Cancer Cells

Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation

Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL

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