Metabolic reprogramming by tobacco-specific nitrosamines (TSNAs) in cancer

Sarlak, Saharnaz; Lalou, Claude; Amoêdo, Nívea Dias; Rossignol, Rodrigue

doi:10.1016/j.semcdb.2019.09.001

Cited by 27 publications

(10 citation statements)

References 187 publications

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“…There are also strong evidences of α7-nAChR involvement in oncogenic transformation and tumor progression upon activation by nicotine ( Grando, 2014 ; Schaal and Chellappan, 2014 ). Nicotine and tobacco nitrosamines [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN)] contained in tobacco smoke cause oncogenic transformation of normal cells ( Arredondo et al, 2006a ) and drive proliferation, migration, and invasion of breast, pancreatic, and lung cancer cells ( Dasgupta et al, 2009 ; Gankhuyag et al, 2017 ; Sarlak et al, 2020 ). Notably, nicotine and nitrosamines demonstrate greater affinity to the α7 receptor than endogenous ACh ( Grando, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

SLURP-1 Controls Growth and Migration of Lung Adenocarcinoma Cells, Forming a Complex With α7-nAChR and PDGFR/EGFR Heterodimer

Bychkov

Shulepko

Shlepova

et al. 2021

Front. Cell Dev. Biol.

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Secreted Ly6/uPAR-related protein 1 (SLURP-1) is a secreted Ly6/uPAR protein that negatively modulates the nicotinic acetylcholine receptor of α7 type (α7-nAChR), participating in control of cancer cell growth. Previously we showed, that a recombinant analogue of human SLURP-1 (rSLURP-1) diminishes the lung adenocarcinoma A549 cell proliferation and abolishes the nicotine-induced growth stimulation. Here, using multiplex immunoassay, we demonstrated a decrease in PTEN and mammalian target of rapamycin (mTOR) kinase phosphorylation in A549 cells upon the rSLURP-1 treatment pointing on down-regulation of the PI3K/AKT/mTOR signaling pathway. Decreased phosphorylation of the platelet-derived growth factor receptor type β (PDGFRβ) and arrest of the A549 cell cycle in the S and G2/M phases without apoptosis induction was also observed. Using a scratch migration assay, inhibition of A549 cell migration under the rSLURP-1 treatment was found. Affinity extraction demonstrated that rSLURP-1 in A549 cells forms a complex not only with α7-nAChR, but also with PDGFRα and epidermal growth factor receptor (EGFR), which are known to be involved in regulation of cancer cell growth and migration and are able to form a heterodimer. Knock-down of the genes encoding α7-nAChR, PDGFRα, and EGFR confirmed the involvement of these receptors in the anti-migration effect of SLURP-1. Thus, SLURP-1 can target the α7-nAChR complexes with PDGFRα and EGFR in the membrane of epithelial cells. Using chimeric proteins with grafted SLURP-1 loops we demonstrated that loop I is the principal active site responsible for the SLURP-1 interaction with α7-nAChR and its antiproliferative effect. Synthetic peptide mimicking the loop I cyclized by a disulfide bond inhibited ACh-evoked current at α7-nAChR, as well as A549 cell proliferation and migration. This synthetic peptide represents a promising prototype of new antitumor drug with the properties close to that of the native SLURP-1 protein.

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Section: Introductionmentioning

confidence: 99%

SLURP-1 Controls Growth and Migration of Lung Adenocarcinoma Cells, Forming a Complex With α7-nAChR and PDGFR/EGFR Heterodimer

Bychkov

Shulepko

Shlepova

et al. 2021

Front. Cell Dev. Biol.

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“…16,17 Chemically, CYP450 reacts with toxic substances present in SLT products to produce reactive intermediates that can damage DNA. 18 During the reaction mechanism of carcinogenesis, NNK reduces to NNAL, CYP-450 reacts with NNAL to form alpha hydroxyl NNAL that produces diazonium ions and aldehydes due to its instability and upon interaction with DNA to form DNA adducts. 18 Impairments in DNA repair mechanism lead to DNA adducts stability that can induce oncogenes or gene silencing of tumor suppressor genes.…”

Section: Introductionmentioning

confidence: 99%

“…18 During the reaction mechanism of carcinogenesis, NNK reduces to NNAL, CYP-450 reacts with NNAL to form alpha hydroxyl NNAL that produces diazonium ions and aldehydes due to its instability and upon interaction with DNA to form DNA adducts. 18 Impairments in DNA repair mechanism lead to DNA adducts stability that can induce oncogenes or gene silencing of tumor suppressor genes. Consequently, these mutations induce cell proliferation and result in carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Structure‐based study to identify alkaloids as promising cytochrome P450 (CYP1A1) inhibitors: An in silico approach using virtual screening, molecular dynamic simulations, and binding free energy calculation

Verma

Bhargava

Sajid

et al. 2022

J of Cellular Biochemistry

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Carcinogens present in smokeless tobacco (SLT) like tobacco-specific nitrosamines can be metabolized by the cytochrome P450 (CYP450) enzyme.Functionally, the CYP450 enzyme resides in a heme pigment to perform the catalytic activity. The CYP1A1 is one of the main extrahepatic CYP450 enzymes known to detoxify toxic substances and activate carcinogens. The CYP1A1 inhibition by potential inhibitors reduce the chance of oral cancer. The current study aimed to explore more about the inhibitor binding site and identification of lead alkaloids, that could work as putative inhibitors against target CYP1A1. In respect, we have performed docking studies, virtual screening of alkaloids, and natural product libraries against CYP1A1 followed by molecular dynamic simulations and binding free energy calculations. Docking studies of tobacco-specific nitrosamine (TSNA) products and their similar carcinogen analogs revealed that the heme group is bound to the floor of the bowl-shaped cavity whereas carcinogens are bound to the roof of the rounded shape cavity. Furthermore, virtual screening and binding free energy calculations revealed Tomatidine as a putative inhibitor against CYP1A1. On the basis of altogether outcomes of the current study, we have concluded that the addition of lead-hit alkaloid Tomatidine and others in SLT products may be working as a supplement that could be able to reduce the expression of human CYP1A1 and suppresses carcinogenic by-products formations.

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“…They are formed during tobacco curing, storage, and fermentation by nitrosation of tobacco alkaloids such as nicotine, nornicotine, anabasine, and anatabine. TSNAs are not present in fresh leaves of tobacco and their formation starts a few days after harvesting (Hecht & Hoffmann 1988;Spiegelhalder & Fischer 1991;Sarlak et al 2020). The TSNAs include 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N'-nitrosonornicotine (NNN), N'-nitrosoanabasine (NAB) and N'-nitrosoanatabine (NAT).…”

Section: Introductionmentioning

confidence: 99%

LC-MS/MS analysis of carcinogenic tobacco-specific nitrosamines in Spodoptera litura using the QuEChERS method

Karthik

Yashaswini

Morthala

et al. 2022

Preprint

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Nicotine is a highly addictive alkaloid and a neurostimulator found in tobacco that causes addiction in humans and makes tobacco a high-demand commercial product. It is popularly used for recreational purposes and is not a harmful substance except for the addiction it causes. The metabolites of nicotine such as the Tobacco-specific Nitrosamines (TSNAs) are hazardous substances whose metabolites are highly electrophilic and form DNA adducts, which will initiate the process of carcinogenesis. TSNAs are formed during curing, storage and fermentation due to the nitrosation of nicotine and other tobacco alkaloids. TSNAs are used as biomarkers for cancer risk assessment in humans exposed to tobacco and its products. To determine the occasional formation of TSNAs in tobacco-feeding insects, 5th instar larvae of Spodoptera litura and their faeces were analyzed for the presence of NNN, NNK, and NNAL along with the stored tobacco leaves (PT-76) using an Agilent 6470B LC-MS/MS system following ISO/DIS 19290:2015 protocol. The LOD and LOQ were 0.001 mg/kg and 0.005 mg/kg for all the tested nitrosamines. NNN was found to be 0.365 mg/kg, 0.344 mg/kg, and 5.71 mg/kg in insect whole-body samples, faeces, and tobacco leaves, respectively. NNK was found to be 0.062 mg/kg, 0.036 mg/kg and 0.97 mg/kg in insect whole body samples, faeces and tobacco leaves, respectively. However, NNAL was not detected in both the insect’s whole body and faeces. Recoveries ranged between 95-98% for all compounds when spiked at LOD and LOQ. The presence of TSNAs is a biomarker for cancer risk and their presence in insects would point to cancer risk assessment in tobacco feeding insects and any possible TSNA-detoxifying pathways in insects that might prevent mutagenesis caused these compounds.

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Metabolic reprogramming by tobacco-specific nitrosamines (TSNAs) in cancer

Cited by 27 publications

References 187 publications

SLURP-1 Controls Growth and Migration of Lung Adenocarcinoma Cells, Forming a Complex With α7-nAChR and PDGFR/EGFR Heterodimer

SLURP-1 Controls Growth and Migration of Lung Adenocarcinoma Cells, Forming a Complex With α7-nAChR and PDGFR/EGFR Heterodimer

Structure‐based study to identify alkaloids as promising cytochrome P450 (CYP1A1) inhibitors: An in silico approach using virtual screening, molecular dynamic simulations, and binding free energy calculation

LC-MS/MS analysis of carcinogenic tobacco-specific nitrosamines in Spodoptera litura using the QuEChERS method

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