Gene Therapy with MiRNA-Mediated Targeting of Mcl-1 Promotes the Sensitivity of Non-Small Cell Lung Cancer Cells to Treatment with ABT-737

Shahverdi, Mahshid; Amini, Razieh; Amri, Jamal; Karami, Hadi

doi:10.31557/apjcp.2020.21.3.675

Cited by 16 publications

(11 citation statements)

References 52 publications

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“…By using a series of biochemical, pharmacological and genetic approaches, we not only demonstrated in this study that MCL-1 up-regulation mediates apoptosis resistance in arsenic and BaP co-exposure-transformed cells, but also showed that down-regulating MCL-1 protein levels in the co-exposure-transformed cells significantly reduces their CSC-like property and tumorigenicity. Previous studies showed that down-regulating MCL-1 protein levels sensitizes lung cancer cells to ABT-737-induced apoptosis 34 , 35 . Our above findings are thus important, not only because they indicate that MCL-1 up-regulation plays a critical role in arsenic and BaP co-exposure-induced tumorigenesis, but also because they suggest that strategies of targeting MCL-1 could be effective in preventing and treating lung cancer resulting from arsenic and BaP co-exposure.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinase USP7-mediated MCL-1 up-regulation enhances Arsenic and Benzo(a)pyrene co-exposure-induced Cancer Stem Cell-like property and Tumorigenesis

Yang

Xie

et al. 2020

Theranostics

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Rationale: MCL-1 is up-regulated in cancer and a target for cancer treatment. How MCL-1 is up-regulated and whether MCL-1 up-regulation plays a role in tumorigenic process is not well-known. Arsenic and benzo(a)pyrene (BaP) are well-recognized lung carcinogens and we recently reported that arsenic and BaP co-exposure acts synergistically in inducing cancer stem cell (CSC)-like property and lung tumorigenesis. This study was performed to further investigate the underlying mechanism focusing on the role of MCL-1. Methods: The spheroid formation assay and nude mouse tumorigenesis assay were used to determine the CSC-like property and tumorigenicity of arsenic plus BaP co-exposure-transformed human bronchial epithelial BEAS-2B cells, respectively. Biochemical, pharmacological and genetic approaches were used to manipulate gene expressions, dissect signaling pathways and determine protein-protein interactions. Both loss-of-function and gain-of-function approaches were used to validate the role of MCL-1 in arsenic plus BaP co-exposure-enhanced CSC-like property and tumorigenicity. Results: Arsenic plus BaP co-exposure-transformed cells express significantly higher protein levels of MCL-1 than the passage-matched control, arsenic or BaP exposure alone-transformed cells. Knocking down MCL-1 levels in arsenic plus BaP co-exposure-transformed cells significantly reduced their apoptosis resistance, CSC-like property and tumorigenicity in mice. Mechanistic studies revealed that arsenic plus BaP co-exposure up-regulates MCL-1 protein levels by synergistically activating the PI3K/Akt/mTOR pathway to increase the level of a deubiquitinase USP7, which in turn reduces the level of MCL-1 protein ubiquitination and prevents its subsequent proteasome degradation. Conclusions: The deubiquitinase USP7-mediated MCL-1 up-regulation enhances arsenic and BaP co-exposure-induced CSC-like property and tumorigenesis, providing the first evidence demonstrating that USP7 stabilizes MCL-1 protein during the tumorigenic process.

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Section: Discussionmentioning

confidence: 99%

Deubiquitinase USP7-mediated MCL-1 up-regulation enhances Arsenic and Benzo(a)pyrene co-exposure-induced Cancer Stem Cell-like property and Tumorigenesis

Yang

Xie

et al. 2020

Theranostics

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“…In apoptotic conditions, the pro-apoptotic members such as Bak and Bax form a homodimer, leading to the change in the mitochondrial outer membrane permeability (MOMP), release of cytochrome c from mitochondria, and subsequently activation of caspases-3, -6 and -7. The anti-apoptotic proteins such as Bcl-2 and Mcl-1, by heterodimerising with Bak and Bax, inhibit apoptosis (Shahverdi et al, 2020a;Shahverdi et al, 2020b). Fludarabine induces apoptosis in vitro systems and in primary CLL cells by inhibiting several enzymes involved in DNA and RNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Fludarabine-Sensitivity in CLL-CII Cells by the members of the Bcl-2 family proteins including the pro-survival members and the pro-apoptotic members (Shahverdi et al, 2020a;Shahverdi et al, 2020b). Upregulation of prosurvival Bcl-2 family members such as Bcl-2 and Mcl-1 is associated with resistance to treatment with fludarabine, chlorambucil and rituximab, as well as shorter overall survival in CLL patients.…”

Section: Mirna-mediated Knock-down Of Bcl-2 and Mcl-1 Increasesmentioning

confidence: 99%

MiRNA-Mediated Knock-Down of Bcl-2 and Mcl-1 Increases Fludarabine-Sensitivity in CLL-CII Cells

Ashofteh

Amini

Molaee

et al. 2021

Asian Pac J Cancer Prev

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Background: Over-expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1 is associated with resistance to chemotherapeutic agents such as fludarabine. Moreover, an inverse relationship between miRNA-15a levels with Bcl-2 and Mcl-1 expression has been observed in CLL patients. In this study, the effect of miRNA-15a on apoptosis and sensitivity of the CLL cells to fludarabine was investigated. Methods: After treatments, the Mcl-1 and Bcl-2 expression levels were quantified by RT-qPCR. Trypan blue assay was used to explore the effects of miRNA-15a and fludarabine on cell proliferation. The cytotoxicity was measured using MTT assay and combination index analysis. Cell death was determined using cell death detection ELISA assay and caspase-3 activity assay Kits. Results: Results showed that miRNA-15a clearly decreased the mRNA levels of Bcl-2 and Mcl-1 in a time dependent manner, which led to CLL-II cell proliferation inhibition and enhancement of apoptosis (p < 0.05, relative to control). Transfection of the miRNA-15a synergistically reduced the cell survival rate and lowered the IC 50 value of fludarabine. Furthermore, miRNA-15a significantly enhanced the apoptotic effect of fludarabine. Conclusions: Our data propose that suppression of Bcl-2 and Mcl-1 by miRNA-15a can effectively inhibit the cell proliferation and sensitize CLL cells to fludarabine. Therefore, miRNA-15a can be considered as a potential therapeutic target in CLL resistant patients.

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“…ABT-737 and Bcl-2 antisense oligonucleotides were developed to trigger apoptosis in the case of NSCLC [45]. Considering the role of TRAIL in LC, rhTRAIL (AMG 951), Mapatumumab (anti-TRAIL-R1 mAb), and AMG 655 have been developed to target the death receptor in the lungs [32].…”

Section: Pi3k/akt/mtor Signaling Pathway and Pi3k/akt/mtor Inhibitors In Lcmentioning

confidence: 99%

Signaling Pathway Inhibitors, miRNA, and Nanocarrier-Based Pharmacotherapeutics for the Treatment of Lung Cancer: A Review

Alhakamy

Karim

et al. 2021

Pharmaceutics

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Lung cancer is one of the most commonly diagnosed cancers and is responsible for a large number of deaths worldwide. The pathogenic mechanism of lung cancer is complex and multifactorial in origin. Thus, various signaling pathways as targets for therapy are being examined, and many new drugs are in the pipeline. However, both conventional and target-based drugs have been reported to present significant adverse effects, and both types of drugs can affect the clinical outcome in addition to patient quality of life. Recently, miRNA has been identified as a promising target for lung cancer treatment. Therefore, miRNA mimics, oncomiRs, or miRNA suppressors have been developed and studied for possible anticancer effects. However, these miRNAs also suffer from the limitations of low stability, biodegradation, thermal instability, and other issues. Thus, nanocarrier-based drug delivery for the chemotherapeutic drug delivery in addition to miRNA-based systems have been developed so that existing limitations can be resolved, and enhanced therapeutic outcomes can be achieved. Thus, this review discusses lung cancer’s molecular mechanism, currently approved drugs, and their adverse effects. We also discuss miRNA biosynthesis and pathogenetic role, highlight pre-clinical and clinical evidence for use of miRNA in cancer therapy, and discussed limitations of this therapy. Furthermore, nanocarrier-based drug delivery systems to deliver chemotherapeutic drugs and miRNAs are described in detail. In brief, the present review describes the mechanism and up-to-date possible therapeutic approaches for lung cancer treatment and emphasizes future prospects to bring these novel approaches from bench to bedside.

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Gene Therapy with MiRNA-Mediated Targeting of Mcl-1 Promotes the Sensitivity of Non-Small Cell Lung Cancer Cells to Treatment with ABT-737

Abstract: interaction between pro-apoptotic and anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins. Anti-apoptotic proteins including Bcl-2 itself, Mcl-1 (myeloid cell leukemia-1), Bcl-w, Bcl-xL, and Bfl-1/A1 promote

Cited by 16 publications

References 52 publications

Deubiquitinase USP7-mediated MCL-1 up-regulation enhances Arsenic and Benzo(a)pyrene co-exposure-induced Cancer Stem Cell-like property and Tumorigenesis

Deubiquitinase USP7-mediated MCL-1 up-regulation enhances Arsenic and Benzo(a)pyrene co-exposure-induced Cancer Stem Cell-like property and Tumorigenesis

MiRNA-Mediated Knock-Down of Bcl-2 and Mcl-1 Increases Fludarabine-Sensitivity in CLL-CII Cells

Signaling Pathway Inhibitors, miRNA, and Nanocarrier-Based Pharmacotherapeutics for the Treatment of Lung Cancer: A Review

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