Titania Nanosheets Generates Peroxynitrite for S-Nitrosylation and Enhanced p53 Function in Lung Cancer Cells

Abstract Background: Metal oxide nanomaterials are increasingly being exploited in cancer therapy thanks to their unique properties, which can enhance the efficacy of current cancer therapies. However, the nanotoxicity and mechanism of Ti0.8O2 nanosheets for specific site-targeting strategies in NSCLC have not yet been investigated.Methods: The effects of Ti0.8O2 nanosheets on cytotoxicity in NSCLC cells and normal cells were examined. The apoptosis characteristics, including condensed and fragmented nuclei, as assessed by positive staining with annexin V. The cellular uptake of the nanosheets and the induction of stress fiber were assessed via transmission electron microscopy (TEM) and scanning electron microscopy (SEM) analyses, respectively. We also evaluated the expression of protein in death mechanism to identify the molecular mechanisms behind the toxicity of these cells. We investigated the relationship between S-nitrosylation and the increase in p53 stability by molecular dynamics.Results: Ti0.8O2 nanosheets caused cytotoxicity in several lung cancer cells, but not in normal cells. The nanosheets could enter lung cancer cells and exert an apoptosis induction. Results for protein analysis further indicated the activation of p53, increased Bax, decreased Bcl-2 and Mcl-1, and activation of caspase-3. The nanosheets also exhibited a substantial apoptosis effect in drug-resistant metastatic primary lung cancer cells, and it was found that the potency of the nanosheets was dramatically higher than that of cisplatin and etoposide. In terms of their mechanism of action, we found that the mode of apoptosis induction was through the generation of cellular ONOO− mediated the S-nitrosylation of p53 at C182. Molecular dynamics analysis further showed that the S-nitrosylation of one C182 stabilized the p53 dimer. Consequently, this nitrosylation of the protein led to an upregulation of p53 through its stabilization.Conclusions: Taking all the evidence together, we provided information on the apoptosis induction effect of the nanosheets through a molecular mechanism involving reactive nitrogen species, which affects the protein stability; thus emphasizing the novel mechanism of action of nanomaterials for cancer therapy.

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Renieramycin T Induces Lung Cancer Cell Apoptosis by Targeting Mcl-1 Degradation: A New Insight in the Mechanism of Action

Marine Drugs ◽

10.3390/md17050301 ◽

2019 ◽

Vol 17 (5) ◽

pp. 301 ◽

Cited By ~ 3

Author(s):

Korrakod Petsri ◽

Supakarn Chamni ◽

Khanit Suwanborirux ◽

Naoki Saito ◽

Pithi Chanvorachote

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Mechanism Of Action ◽

Targeted Therapies ◽

P53 Protein ◽

Myeloid Cell ◽

Lung Cancer Cells ◽

Apoptosis Induction ◽

Cancer Cell Survival

Among malignancies, lung cancer is the major cause of cancer death. Despite the advance in lung cancer therapy, the five-year survival rate is extremely restricted due to therapeutic failure and disease relapse. Targeted therapies selectively inhibiting certain molecules in cancer cells have been accepted as promising ways to control cancer. In lung cancer, evidence has suggested that the myeloid cell leukemia 1 (Mcl-1) protein, an anti-apoptotic member of the Bcl-2 family, is a target for drug action. Herein, we report the Mcl-1 targeting activity of renieramycin T (RT), a marine-derived tetrahydroisoquinoline alkaloid that was isolated from the Thai blue sponge Xestospongia sp. RT was shown to be dominantly toxic to lung cancer cells compared to the normal cells in the lung. The cytotoxicity of this compound toward lung cancer cells was mainly exerted through apoptosis induction. For the mechanism of action, we found that RT mediated activation of p53 protein and caspase-9 and -3 activations. While others Bcl-2 family proteins (Bcl-2, Bak, and Bax) were minimally changed in response to RT, Mcl-1 protein was dramatically diminished. We further performed the cycloheximide experiment and found that the half-life of Mcl-1 was significantly shortened by RT treatment. When MG132, a potent selective proteasome inhibitor, was utilized, it could restore the Mcl-1 level. Furthermore, immunoprecipitation analysis revealed that RT significantly increased the formation of Mcl-1-ubiquitin complex compared to the non-treated control. In conclusion, we report the potential apoptosis induction of RT with a mechanism of action involving the targeting of Mcl-1 for ubiquitin-proteasomal degradation. As Mcl-1 is critical for cancer cell survival and chemotherapeutic failure, this novel information regarding the Mcl-1-targeted compound would be beneficial for the development of efficient anti-cancer strategies or targeted therapies.

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Nuclear Transglutaminase 2 interacts with topoisomerase II⍺ to promote DNA damage repair in lung cancer cells

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02009-2 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xiao Lei ◽

Kun Cao ◽

Yuanyuan Chen ◽

Hui Shen ◽

Zhe Liu ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Cancer Therapy ◽

Cancer Cells ◽

Protein Localization ◽

Transglutaminase 2 ◽

Lung Cancer Cells ◽

Mass Spectrometry Analysis ◽

Cancer Resistance ◽

Dsb Repair

Abstract Background To block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death. DSB repair depends on a sequential activation of DNA repair factors that may be potentially targeted for clinical cancer therapy. Up to now, many protein components of DSB repair complex remain unclear or poorly characterized. In this study, we discovered that Transglutaminase 2 (TG2) acted as a new component of DSB repair complex. Methods A bioinformatic analysis was performed to identify DNA damage relative genes from dataset from The Cancer Genome Atlas. Immunofluorescence and confocal microscopy were used to monitor the protein localization and recruitment kinetics. Furthermore, immunoprecipitation and mass spectrometry analysis were performed to determine protein interaction of both full-length and fragments or mutants in distinct domain. In situ lung cancer model was used to study the effects cancer therapy in vivo. Results After DSB induction, cytoplasmic TG2 was extensively mobilized and translocated into nucleus after phosphorylated at T162 site by DNA-PKcs. Nuclear TG2 quickly accumulated at DSB sites and directly interacting with Topoisomerase IIα (TOPOIIα) with its TGase domain to promote DSB repair. TG2 deficient cells lost capacity of DSB repair and become susceptible to ionizing radiation. Specific inhibition of TG2-TOPOIIα interaction by glucosamine also significantly inhibited DSB repair, which increased sensitivity in lung cancer cells and engrafted lung cancers. Conclusions These findings elucidate new mechanism of TG2 in DSB repair trough directly interacting with TOPOIIα, inhibition of which provided potential target for overcoming cancer resistance.

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Peroxide Is a Key Mediator of Bcl-2 Down-Regulation and Apoptosis Induction by Cisplatin in Human Lung Cancer Cells

Molecular Pharmacology ◽

10.1124/mol.107.040873 ◽

2007 ◽

Vol 73 (1) ◽

pp. 119-127 ◽

Cited By ~ 40

Author(s):

Liying Wang ◽

Pithi Chanvorachote ◽

David Toledo ◽

Christian Stehlik ◽

Robert R. Mercer ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Human Lung ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Apoptosis Induction ◽

Down Regulation ◽

Human Lung Cancer Cells

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ErbB4 increases the proliferation potential of human lung cancer cells and its blockage can be used as a target for anti-cancer therapy

International Journal of Cancer ◽

10.1002/ijc.21818 ◽

2006 ◽

Vol 119 (2) ◽

pp. 269-274 ◽

Cited By ~ 35

Author(s):

Alex Starr ◽

Joel Greif ◽

Akiva Vexler ◽

Maia Ashkenazy-Voghera ◽

Valery Gladesh ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Therapy ◽

Cancer Cells ◽

Human Lung ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Anti Cancer ◽

Human Lung Cancer Cells ◽

Proliferation Potential

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Cell autonomous angiotensin II signaling controls the pleiotropic functions of oncogenic K-Ras

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015188 ◽

2020 ◽

pp. jbc.RA120.015188

Author(s):

Daniela Volonte ◽

Morgan Sedorovitz ◽

Victoria E. Cespedes ◽

Maria L. Beecher ◽

Ferruccio Galbiati

Keyword(s):

Lung Cancer ◽

Angiotensin Ii ◽

Cancer Cells ◽

Lung Tumor ◽

Tumor Formation ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Dependent Manner ◽

Ang Ii ◽

Normal Cells

Oncogenic K-Ras (K-RasG12V) promotes senescence in normal cells but fuels transformation of cancer cells after the senescence barrier is bypassed. The mechanisms regulating this pleiotropic function of K-Ras remain to be fully established and bear high pathological significance. We find that K-RasG12V activates the angiotensinogen (AGT) gene promoter and promotes AGT protein expression in a Kruppel Like Factor 6 (KLF6)-dependent manner in normal cells. We show that AGT is then converted to angiotensin II (Ang II) in a cell-autonomous manner by cellular proteases. We show that blockade of the Ang II receptor type 1 (AT1-R) in normal cells inhibits oncogene-induced senescence (OIS). We provide evidence that the oncogenic K-Ras-induced synthesis of Ang II and AT1-R activation promote senescence through caveolin-1-dependent and NOX2-mediated oxidative stress. Interestingly, we find that expression of AGT remains elevated in lung cancer cells but in a KLF6-independent and High Mobility Group AT-Hook 1 (HMGA1)-dependent manner. We show that Ang II-mediated activation of the AT1-R promotes cell proliferation and anchorage-independent growth of lung cancer cells through a STAT3-dependent pathway. Finally, we find that expression of AGT is elevated in lung tumors of K-RasLA2-G12D mice, a mouse model of lung cancer, and human lung cancer. Treatment with the AT1-R antagonist losartan inhibits lung tumor formation in K-RasLA2-G12D mice. Together, our data provide evidence of the existence of a novel cell-autonomous and pleiotropic Ang II-dependent signaling pathway through which oncogenic K-Ras promotes OIS in normal cells while fueling transformation in cancer cells.

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Improving Combination Cancer Therapy by Acetaminophen and Romidepsin in Non-small Cell Lung Cancer Cells

Biomedical Science Letters ◽

10.15616/bsl.2019.25.4.293 ◽

2019 ◽

Vol 25 (4) ◽

pp. 293-301

Author(s):

Seong-Min Lee ◽

James S. Park ◽

Keun-Sik Kim

Keyword(s):

Lung Cancer ◽

Cancer Therapy ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Small Cell ◽

Lung Cancer Cells ◽

Small Cell Lung ◽

Combination Cancer Therapy

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Screening for Selective Anticancer Activity of 65 Extracts of Plants Collected in Western Andalusia, Spain

10.20944/preprints201806.0177.v1 ◽

2018 ◽

Cited By ~ 1

Author(s):

José Manuel Calderón-Montaño ◽

Sara María Martínez-Sánchez ◽

Estefanía Burgos-Morón ◽

Emilio Guillén-Mancina ◽

Julio José Jiménez-Alonso ◽

...

Keyword(s):

Lung Cancer ◽

Cytotoxic Activity ◽

Anticancer Activity ◽

Cancer Cells ◽

Cell Lines ◽

Selectivity Index ◽

Lung Cancer Cells ◽

Taxus Baccata ◽

Normal Cells ◽

Tetraclinis Articulata

In our continuous search for selective anticancer treatments, we have screened 65 extracts from 45 plants collected in several areas of Western Andalusia (Spain) for cytotoxic activity against lung cancer cells and lung normal cells. Active extracts were also tested against 11 cell lines from other tissues. An extract from the leaves of Tetraclinis articulata (Vahl) Mast. (Cupressaceae) showed a marked cytotoxicity (IC50 = 0.37 ± 0.03 µg/mL) and selectivity (selectivity index = 378.3) against the lung cancer cells; cisplatin, 5-fluorouracil and an extract from the leaves of Taxus baccata L. (Taxaceae) were less cytotoxic and selective.

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Characterization of a lung cancer growth factor, LASEP1, as a serologic and prognostic biomarker and a therapeutic target.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.11104 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 11104-11104

Author(s):

Atsushi Takano ◽

Yusuke Nakamura ◽

Yataro Daigo

Keyword(s):

Lung Cancer ◽

Healthy Volunteers ◽

Cancer Cells ◽

Serum Protein ◽

Therapeutic Target ◽

Culture Media ◽

Lung Cancer Cells ◽

Positive Staining ◽

Lung Cancers

11104 Background: Identification and evaluation of oncoproteins are an effective approaches to develop novel diagnostic/prognostic biomarkers or therapeutic targets. Methods: We established a strategy as follows. i)To identify up-regulated genes in non-small cell lung cancers (NSCLCs) using the cDNA microarray, ii) To verify the candidate genes for their no or low expression in 23 normal tissues by northern-blot, iii)To validate clinicopathological significance of their protein expression by tissue microarray, iv)To verify whether they are essential for the growth of cancer cells by siRNA, and v)To measure their serum protein levels by ELISA. Results: We identified LASEP1 (Lung cancer Associated Serum Protein 1) as a candidate target molecule. Immunohistochemical staining using tumor tissue microarrays consisting of 374 NSCLC confirmed positive staining of LASEP1 was observed in 210 (56.1%) of 374 NSCLC. In addition, a high level of LASEP1 expression was associated with poor prognosis of NSCLC patients. Serum LASEP1 levels were higher in NSCLC than in healthy volunteers. The proportion of serum LASEP1-positive cases was 127 (38.6%) of 329 lung cancers, while 4 (3.9%) of 102 healthy volunteers were falsely diagnosed. Furthermore, treatment of lung cancer cells with siRNAs against LASEP1 suppressed its expression and resulted in growth suppression of the lung cancer cells; on the other hand, induction of exogenous expression of LASEP1 conferred growth-promoting activity in vitro. We found its 50-kDa receptor (LASEPR) which interacts with LASEP1 on lung cancer cell surface. Suppression of LASEPR expression by siRNAs inhibited the growth of cancer cells. The LASEP1-LASEPR interaction promoted the cell growth in an autocrine manner. In addition, the growth activity of the LASEP1-positive cells was neutralized by the addition of originally developed anti-LASEP1 monoclonal antibodies into their culture media. The systemic administration of the anti-LASEP1 antibody to tumor-implanted mice significantly suppressed tumor growth without any adverse events. Conclusions: We have identified LASEP1 as potential targets for development of biomarkers and therapeutic target for lung cancer.

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ATP promotes cell survival via regulation of cytosolic [Ca2+] and Bcl-2/Bax ratio in lung cancer cells

AJP Cell Physiology ◽

10.1152/ajpcell.00092.2015 ◽

2016 ◽

Vol 310 (2) ◽

pp. C99-C114 ◽

Cited By ~ 33

Author(s):

Shanshan Song ◽

Krista N. Jacobson ◽

Kimberly M. McDermott ◽

Sekhar P. Reddy ◽

Anne E. Cress ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Progression ◽

Intracellular Signaling ◽

Airway Epithelial Cells ◽

Lung Cancer Cells ◽

Plateau Phase ◽

Normal Cells ◽

Cell Functions

Adenosine triphosphate (ATP) is a ubiquitous extracellular messenger elevated in the tumor microenvironment. ATP regulates cell functions by acting on purinergic receptors (P2X and P2Y) and activating a series of intracellular signaling pathways. We examined ATP-induced Ca2+ signaling and its effects on antiapoptotic (Bcl-2) and proapoptotic (Bax) proteins in normal human airway epithelial cells and lung cancer cells. Lung cancer cells exhibited two phases (transient and plateau phases) of increase in cytosolic [Ca2+] ([Ca2+]cyt) caused by ATP, while only the transient phase was observed in normal cells. Removal of extracellular Ca2+ eliminated the plateau phase increase of [Ca2+]cyt in lung cancer cells, indicating that the plateau phase of [Ca2+]cyt increase is due to Ca2+ influx. The distribution of P2X (P2X1-7) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11) receptors was different between lung cancer cells and normal cells. Proapoptotic P2X7 was nearly undetectable in lung cancer cells, which may explain why lung cancer cells showed decreased cytotoxicity when treated with high concentration of ATP. The Bcl-2/Bax ratio was increased in lung cancer cells following treatment with ATP; however, the antiapoptotic protein Bcl-2 demonstrated more sensitivity to ATP than proapoptotic protein Bax. Decreasing extracellular Ca2+ or chelating intracellular Ca2+ with BAPTA-AM significantly inhibited ATP-induced increase in Bcl-2/Bax ratio, indicating that a rise in [Ca2+]cyt through Ca2+ influx is the critical mediator for ATP-mediated increase in Bcl-2/Bax ratio. Therefore, despite high ATP levels in the tumor microenvironment, which would induce cell apoptosis in normal cells, the decreased P2X7 and elevated Bcl-2/Bax ratio in lung cancer cells may enable tumor cells to survive. Increasing the Bcl-2/Bax ratio by exposure to high extracellular ATP may, therefore, be an important selective pressure promoting transformation and cancer progression.

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