Regulation of Bax-dependent apoptosis by mitochondrial deubiquitinase USP30

AbstractDeubiquitinates (DUBs) have been suggested as novel promising targets for cancer therapies. Accumulating experimental evidence suggests that some metal compounds have the potential to induce cancer cell death via inhibition of DUBs. We previously reported that auranofin, a gold(I)-containing agent used for the treatment of rheumatoid arthritis in clinics, can induce cell death by inhibiting proteasomal DUBs in a series of cancer cell lines. Unfortunately, currently available gold compounds are not potent in inhibiting DUBs. Here, we report that: (i) aumdubin, a synthetic derivative of auranofin, exhibited stronger DUB-inhibiting and apoptosis-inducing activities than auranofin in lung cancer cells; (ii) aumdubin shows high affinity for mitochondrial DUB USP30; (iii) aumdubin induces apoptosis by increasing the ubiquitination and mitochondrial location of Bax protein; and (iv) USP30 inhibition may contribute to Bax-dependent apoptosis induced by aumdubin in lung cancer cells. These results suggest that gold(I)-containing agent aumdubin induces Bax-dependent apoptosis partly through inhibiting the mitochondrial DUB USP30, which could open new avenues for lung cancer therapy.

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Fluorinated thiazolidinols cause cell death in A549 lung cancer cells via PI3K/AKT/mTOR and MAPK/ERK signalling pathways

MedChemComm ◽

10.1039/c5md00603a ◽

2016 ◽

Vol 7 (6) ◽

pp. 1197-1203 ◽

Cited By ~ 1

Author(s):

Ravindra M. Kumbhare ◽

Tulshiram L. Dadmal ◽

Dinesh Kumar ◽

M. Janaki Ramaiah ◽

Anudeep Kota ◽

...

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

Lung Cancer Cells ◽

Signalling Pathways ◽

Lung Cancer Cell ◽

Cancer Cell Death ◽

A549 Lung Cancer Cell ◽

A549 Lung

Fluorinated thiazolidinols cause A549 lung cancer cell death by acting via PI3K/Akt/mTOR and MEK/ERK pathways.

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Biosynthesized CdS Nanoparticle Induces ROS-dependent Apoptosis in Human Lung Cancer Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666211115113226 ◽

2021 ◽

Vol 21 ◽

Author(s):

Tina Nasrin ◽

Mousumi Patra ◽

Sayed Modinur Rahaman ◽

Tapan Kumar Das ◽

Soni Shaikh

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

Lung Cancer Cells ◽

World Health ◽

Human Lung Cancer ◽

Ros Production ◽

Lung Cancer Cell ◽

Cancer Cell Death

Background: The World Health Organization (WHO) estimated that the number of cancer-related deaths was 9.6 million in 2018 and 2.09 million deaths occurred by lung cancer. The American Institute for Cancer Research (AICR) also observed gender preferences in lung cancer, common in men than women. Since the past decade, nanoparticles have now been widely documented for their anti-cancer properties, which signifies that the development of nanotechnology would be a future diagnosis and treatment strategy for lung cancer. Objective: The current study aimed to investigate the role of biosynthesized CdS nanoparticles (CdS NPs) in lung cancer cells (A549). Therefore, whether the CdS NP induces lung cancer cell death and the underlying mechanism is yet to be elucidated. Methods: Literature was searched from various archives of biomedical and life science journals. Then, CdS NPs were biosynthesized and characterized by traditional and cutting-edge protocols. The CdS NP-mediated cell death was elucidated following standard protocols. Results : CdS NPs induced cytotoxicity towards A549 cells in a dose-dependent manner. However, such a death mechanism does not go through necrosis. Intracellular reactive oxygen species (ROS) accumulation and mitochondrial membrane depolarization demonstrated that cell death is associated with intracellular ROS production. Furthermore, increased sub-G1 population, Bax expression, and decreased Bcl-2 expression revealed that the death was caused by apoptosis. Conclusion: CdS NPs promote apoptosis-mediated lung cancer cell death through ROS production.

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Anticancer Effects of Auranofin in Human Lung Cancer Cells Through Increasing Intracellular ROS Levels and GSH Depletion

10.21203/rs.3.rs-369523/v1 ◽

2021 ◽

Author(s):

Sun Hyang Park ◽

Xia Ying Cui ◽

Woo Hyun Park

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

A549 Cells ◽

Thioredoxin Reductase ◽

Lung Cancer Cells ◽

Blue Staining ◽

Lung Cancer Cell

Abstract Purpose Auranofin is known to inhibit thioredoxin reductase (TrxR) and has promising anticancer activity in several cancer types. However, at present, there is no clear explanation for the mechanism underlying the inhibitory effects of Auranofin on lung cancer cell growth. In this study, we evaluated the antigrowth effects of Auranofin in cells from various lung cancer cell lines with regard to cell death, reactive oxygen species (ROS), and glutathione (GSH) levels.Methods Cell proliferation was assessed using the trypan blue staining cell counting. ROS levels including O2·-, GSH levels, and MMP (∆Ψm) loss were measured using a flow cytometry. Apoptosis was determined with annexin V-PI staining assay and the change of apoptosis-related protein level was detected by western blotting. TrxR activity was evaluated using a thioredoxin reductase colorimetric assay kit.Results Treatment with Auranofin inhibited cell proliferation and induced cell death based on cell number at 24 h in Calu-6, A549, SK-LU-1, NCI-H460, and NCI-H1299 cells. In addition, Auranofin led to increased ROS levels including O2·- and GSH depletion in these cells. Treatment with N-acetyl cysteine (NAC) attenuated the growth inhibition, mitochondrial membrane potential (MMP, ∆Ψm) loss, and increased ROS levels and GSH depletion in Auranofin-treated Calu-6 and A549 cells. By contrast, L-buthionine sulfoximine (BSO) enhanced cell death, MMP (∆Ψm) loss, ROS production, and GSH depletion. Furthermore, the western blot analysis indicated that Auranofin-induced caspase-3 activation and poly (ADP ribose) polymerase (PARP) cleavage, both of which were prevented by pretreatment with NAC but enhanced by pretreatment with BSO in Calu-6 and A549 cells. Consistent with these changes, the decrease in TrxR activity caused by Auranofin was enhanced by preincubation with BSO and restored in response to the preincubation with NAC in both Calu-6 and A549 cells.Conclusion Our present findings demonstrate that Auranofin-induced cell death is tightly related to oxidative stress in lung cancer cells.

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Effect of S14161 Small Molecule and Glaucium Flavum Extract on A549 Cancer Cells

Galen Medical Journal ◽

10.31661/gmj.v10i0.2151 ◽

2021 ◽

Vol 10 ◽

pp. e2151

Author(s):

Mahshad Kalantari ◽

Maliheh Entezari ◽

Milad Ashrafizadeh ◽

Abolfazl Movafagh ◽

Kiavash Hushmandi

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

Small Molecule ◽

Lethal Effect ◽

Herbal Remedies ◽

Drug Candidates ◽

Cancer Cell Death ◽

Common Cancer

Background: Lung cancer is the fifth most common cancer in Iran. Due to the side effects of common cancer treatments, everyone has turned to herbal remedies and new treatments. This study aimed to compare the effect of S14161 small molecule and Glaucium flavum extract on the induction of apoptosis in A549 cancer cells. Materials and Methods: In this experimental study, the A549 cell line was treated with different concentrations of G. flavum and S14161 on days 1, 3, and 5. Also, half maximal inhibitory concentrations (IC 50) for both G. flavum and S14161 were measured. In addition, the quantitative real-time polymerase chain reaction (qRT-PCR) assay was used to investigate the effects of S14161 and G. flavum extract on the expressions level of Bax, Bad, P53, and Bcl2 genes. Results: Results showed that both the combination of S14161 and G. flavum extract resulted in cell death and reduced cancer cell viability. Nevertheless, the viability rate was greater by S14161, and this small molecule significantly increased the expression of Bax, P53, and Bad apoptotic genes and decreased the expression of the Bcl2 gene, which shows the induced apoptotic death and lethal effect of S14161 in comparison with G. flavum extract. Conclusion: Our study showed that S14161 had fewer IC50 and caused cell death by inhibiting the PI3K/AKT pathway, and G. flavum caused cancer cell death due to its alkaloid compounds. Therefore, both compounds are recommended as drug candidates for the treatment of lung cancer.

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Circular RNA FLNA acts as a sponge of miR-486-3p in promoting lung cancer progression via regulating XRCC1 and CYP1A1

Cancer Gene Therapy ◽

10.1038/s41417-021-00293-w ◽

2021 ◽

Author(s):

Jiongwei Pan ◽

Gang Huang ◽

Zhangyong Yin ◽

Xiaoping Cai ◽

Enhui Gong ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Lung Cancer Cells ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Related Factors

AbstractSignificantly high-expressed circFLNA has been found in various cancer cell lines, but not in lung cancer. Therefore, this study aimed to explore the role of circFLNA in the progression of lung cancer. The target gene of circFLNA was determined by bioinformatics and luciferase reporter assay. Viability, proliferation, migration, and invasion of the transfected cells were detected by CCK-8, colony formation, wound-healing, and transwell assays, respectively. A mouse subcutaneous xenotransplanted tumor model was established, and the expressions of circFLNA, miR-486-3p, XRCC1, CYP1A1, and related genes in the cancer cells and tissues were detected by RT-qPCR, Western blot, or immunohistochemistry. The current study found that miR-486-3p was low-expressed in lung cancer. MiR-486-3p, which has been found to target XRCC1 and CYP1A1, was regulated by circFLNA. CircFLNA was located in the cytoplasm and had a high expression in lung cancer cells. Cancer cell viability, proliferation, migration, and invasion were promoted by overexpressed circFLNA, XRCC1, and CYP1A1 but inhibited by miR-486-3p mimic and circFLNA knockdown. The weight of the xenotransplanted tumor was increased by circFLNA overexpression yet reduced by miR-486-3p mimic. Furthermore, miR-486-3p mimic reversed the effect of circFLNA overexpression on promoting lung cancer cells and tumors and regulating the expressions of miR-486-3p, XRCC1, CYP1A1, and metastasis/apoptosis/proliferation-related factors. However, overexpressed XRCC1 and CYP1A1 reversed the inhibitory effect of miR-486-3p mimic on cancer cells and tumors. In conclusion, circFLNA acted as a sponge of miR-486-3p to promote the proliferation, migration, and invasion of lung cancer cells in vitro and in vivo by regulating XRCC1 and CYP1A1.

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Magneto Mitochondrial Dysfunction Mediated Cancer Cell Death Using Intracellular Magnetic Nano-Transducers

Biomaterials Science ◽

10.1039/d1bm00419k ◽

2021 ◽

Author(s):

Wooram Park ◽

Seok-Jo Kim ◽

Paul Cheresh ◽

Jeanho Yun ◽

Byeongdu Lee ◽

...

Keyword(s):

Cell Death ◽

Cancer Therapy ◽

Mitochondrial Dysfunction ◽

Cancer Cells ◽

Cancer Cell ◽

High Sensitivity ◽

Intrinsic Pathway ◽

Cancer Cell Death

Mitochondria are crucial regulators of the intrinsic pathway of cancer cell death. The high sensitivity of cancer cells to mitochondrial dysfunction offers opportunities for emerging targets in cancer therapy. Herein,...

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17-Allylamino-17-Demethoxygeldanamycin Synergistically Potentiates Tumor Necrosis Factor–Induced Lung Cancer Cell Death by Blocking the Nuclear Factor-κB Pathway

Cancer Research ◽

10.1158/0008-5472.can-05-2698 ◽

2006 ◽

Vol 66 (2) ◽

pp. 1089-1095 ◽

Cited By ~ 82

Author(s):

Xia Wang ◽

Wei Ju ◽

Jordan Renouard ◽

James Aden ◽

Steven A. Belinsky ◽

...

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Tumor Necrosis Factor ◽

Cancer Cell ◽

Tumor Necrosis ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Lung Cancer Cell ◽

Cancer Cell Death ◽

Necrosis Factor

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Tubulin acetylation enhances lung cancer resistance to paclitaxel-induced cell death through Mcl-1 stabilization

Cell Death Discovery ◽

10.1038/s41420-021-00453-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Onsurang Wattanathamsan ◽

Rawikorn Thararattanobon ◽

Ratchanee Rodsiri ◽

Pithi Chanvorachote ◽

Chanida Vinayanuwattikun ◽

...

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Cancer Cells ◽

Trichostatin A ◽

Primary Lung Cancer ◽

Lung Cancer Cells ◽

Cancer Resistance ◽

Apoptosis Resistance ◽

Tubulin Acetylation ◽

Cancer Aggressiveness

AbstractThe posttranslational modifications (PTMs) of microtubules have been reported to play an important role in cancer aggressiveness, including apoptosis resistance. In this study, we aimed to investigate the biological role of microtubule PTMs in the regulation of paclitaxel responsiveness. The acetylated tubulin (Ace-tub) level was strongly associated with paclitaxel sensitivity, as observed in patient-derived primary lung cancer cells and xenografted immunodeficient mice. We showed that paclitaxel-resistant H460 lung cancer cells, generated by a stepwise increase in paclitaxel, exhibited markedly increased tubulin acetylation and consequently acquired paclitaxel resistance. Upregulation of tubulin acetylation by overexpression of α-tubulin acetyltransferase 1 wild-type (αTAT1wt), an enzyme required for acetylation, or by treatment with trichostatin A (TSA), a histone deacetylase 6 (HDAC6) inhibitor, significantly attenuated paclitaxel-induced apoptosis. Investigation of the underlying mechanism revealed that the levels of antiapoptotic Mcl-1 appeared to increase in αTAT1wt-overexpressing and TSA-treated cells compared to control cells, whereas the levels of other antiapoptotic regulatory proteins were unchanged. On the other hand, decreased tubulin acetylation by αTAT1 RNA interference downregulated Mcl-1 expression in patient-derived primary lung cancer and paclitaxel-resistant lung cancer cells. A microtubule sedimentation assay demonstrated that Mcl-1 binds to microtubules preferentially at Ace-type, which prolongs the Mcl-1 half-life (T1/2). Furthermore, immunoprecipitation analysis revealed that polyubiquitination of Mcl-1 was extensively decreased in response to TSA treatment. These data indicate that tubulin acetylation enhances the resistance to paclitaxel-induced cell death by stabilizing Mcl-1 and protecting it from ubiquitin–proteasome-mediated degradation.

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