Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress

Estrogen and secondhand smoke are key risk factors for nonsmoking female lung cancer patients who frequently have lung adenocarcinoma and show tumor estrogen receptor α (ERα) expression. We speculated that estrogen and secondhand smoke might cause harmful effects via ERα signaling. Our results showed that 17β-estradiol (E2), the primary form of endogenous estrogen, exacerbated proliferation, migration, and granzyme B resistance of lung adenocarcinoma cells in an ERα-dependent manner. Cigarette sidestream smoke particulate matter (CSSP), the major component of secondhand smoke, could activate ERα activity dose dependently in human lung adenocarcinoma cells. The estrogenic activity of CSSP was abolished by an ERα-selective antagonist. CSSP regulated the nuclear entry, phosphorylation, and turnover of ERα similarly to E2. Furthermore, CSSP enhanced E2-stimulated ERα activity and Ser118 phosphorylation even when ERα became saturated with E2. Activation of ERα by CSSP required GSK3β activity, but not involving polycyclic aromatic hydrocarbons, reactive oxygen species, calcium, epidermal growth factor receptor, and PI3K/Akt. Although CSSP possessed cytotoxicity, ERα-expressing cells grew and migrated faster than nonexpressing cells on recovery from CSSP exposure as observed in E2-pretreated cells. Knockdown of ERα by siRNA diminished E2- and CSSP-stimulated cell migration. Twenty-one genes, including SERPINB9, were identified to be upregulated by both E2 and CSSP via ERα. Increased SERPINB9 expression was accompanied with increased resistance to granzyme B-mediated apoptosis. This study demonstrates that estrogen has ERα-dependent tumor-promoting activity. CSSP acts like estrogen and shows a potential to enhance estrogen-induced ERα action.

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The curcuminoid CLEFMA selectively induces cell death in H441 lung adenocarcinoma cells via oxidative stress

Investigational New Drugs ◽

10.1007/s10637-010-9610-4 ◽

2010 ◽

Vol 30 (2) ◽

pp. 558-567 ◽

Cited By ~ 11

Author(s):

Kaustuv Sahoo ◽

Mikhail G. Dozmorov ◽

Shrikant Anant ◽

Vibhudutta Awasthi

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Lung Adenocarcinoma ◽

Adenocarcinoma Cells ◽

Lung Adenocarcinoma Cells

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Santamarine Inhibits NF-κB Activation and Induces Mitochondrial Apoptosis in A549 Lung Adenocarcinoma Cells via Oxidative Stress

BioMed Research International ◽

10.1155/2017/4734127 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Xuefeng Wu ◽

Hua Zhu ◽

Jingzhe Yan ◽

Muhammad Khan ◽

Xiuyan Yu

Keyword(s):

Oxidative Stress ◽

Lung Adenocarcinoma ◽

Anticancer Activity ◽

Molecular Mechanism ◽

Dependent Manner ◽

Adenocarcinoma Cells ◽

Lung Adenocarcinoma Cells ◽

Induced Apoptosis ◽

Dose Dependent ◽

A549 Lung

Santamarine (STM), a sesquiterpene lactone component of Magnolia grandiflora and Ambrosia confertiflora, has been shown to possess antimicrobial, antifungal, antibacterial, anti-inflammatory, and anticancer activities. However, no study has yet been conducted to investigate the molecular mechanism of STM-mediated anticancer activity. In the present study, we found that STM inhibits growth and induces apoptosis in A549 lung adenocarcinoma cells through induction of oxidative stress. STM induces oxidative stress by promoting reactive oxygen species (ROS) generation, depleting intracellular glutathione (GSH), and inhibiting thioredoxin reductase (TrxR) activity in a dose-dependent manner. Further mechanistic study demonstrated that STM induces apoptosis by modulation of Bax/Bcl-2 expressions, disruption of mitochondrial membrane potential, activation of caspase-3, and cleavage of PARP in a dose-dependent manner. Moreover, STM inhibited the constitutive and inducible translocation of NF-κBp65 into the nucleus. IKK-16 (I-κB kinase inhibitor) augmented the STM-induced apoptosis, indicating that STM induces apoptosis in A549 cells at least in part through NF-κB inhibition. Finally, STM-induced apoptosis and expressions of apoptosis regulators were effectively inhibited by thiol antioxidant N-acetyl-L-cysteine (NAC), indicating that STM exerts its anticancer effects mainly through oxidative stress. To the best of our knowledge, this is the first report providing evidence of anticancer activity and molecular mechanism of STM.

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Reduced tumor burden through increased oxidative stress in lung adenocarcinoma cells of PARP-1 and PARP-2 knockout mice

Biochimie ◽

10.1016/j.biochi.2015.11.030 ◽

2016 ◽

Vol 121 ◽

pp. 278-286 ◽

Cited By ~ 6

Author(s):

Mercè Mateu-Jiménez ◽

Blanca Cucarull-Martínez ◽

Jose Yelamos ◽

Esther Barreiro

Keyword(s):

Oxidative Stress ◽

Lung Adenocarcinoma ◽

Knockout Mice ◽

Tumor Burden ◽

Adenocarcinoma Cells ◽

Lung Adenocarcinoma Cells ◽

Parp 1

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Proscillaridin A Promotes Oxidative Stress and ER Stress, Inhibits STAT3 Activation, and Induces Apoptosis in A549 Lung Adenocarcinoma Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/3853409 ◽

2018 ◽

Vol 2018 ◽

pp. 1-17 ◽

Cited By ~ 17

Author(s):

Amara Maryam ◽

Tahir Mehmood ◽

Qiulong Yan ◽

Yongming Li ◽

Muhammad Khan ◽

...

Keyword(s):

Oxidative Stress ◽

Lung Adenocarcinoma ◽

Er Stress ◽

Anticancer Activity ◽

Sh2 Domain ◽

Ros Generation ◽

Proscillaridin A ◽

Adenocarcinoma Cells ◽

Lung Adenocarcinoma Cells ◽

A549 Lung

Cardiac glycosides are natural compounds used for the treatment of cardiovascular disorders. Although originally prescribed for cardiovascular diseases, more recently, they have been rediscovered for their potential use in the treatment of cancer. Proscillaridin A (PSD-A), a cardiac glycoside component of Urginea maritima, has been reported to exhibit anticancer activity. However, the cellular targets and anticancer mechanism of PSD-A in various cancers including lung cancer remain largely unexplored. In the present study, we found that PSD-A inhibits growth and induces apoptosis in A549 lung adenocarcinoma cells. The anticancer activity of PSD-A was found to be associated with the activation of JNK, induction of ER stress, mitochondrial dysfunction, and inhibition of STAT3 activation. PSD-A induces oxidative stress as evidenced from ROS generation, GSH depletion, and decreased activity of TrxR1. PSD-A-mediated ER stress was verified by increased phosphorylation of eIF2α and expression of its downstream effector proteins ATF4, CHOP, and caspases-4. PSD-A triggered apoptosis by inducing JNK (1/2) activation, increasing bax/bcl-2 ratio, dissipating mitochondrial membrane potential, and inducing cleavage of caspases and PARP. Further study revealed that PSD-A inhibits both constitutive and inducible STAT3 activations and decreases STAT3 DNA-binding activity. Moreover, PSD-A-mediated inhibition of STAT3 activation was found to be associated with increased SHP-1 expression, decreased phosphorylation of Src, and binding of PSD-A with STAT3 SH2 domain. Finally, STAT3 knockdown by shRNA inhibited growth and enhanced apoptotic efficacy of PSD-A. Taken together, the data suggest that PSD-A could be developed into a potential therapeutic agent against lung adenocarcinoma.

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