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Nicotine is Insufficient as a Carcinogen, It’s Functions as a Tumor Promoter on Purpose

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Jia-Ping Wu at Shaoguan University Medical College
Jia-Ping Wu
  • Shaoguan University Medical College
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Abstract

Nicotine constitutes approximately 0.6~3.0% of the dry weight of tobacco. Like anything that enters the body, nicotine is also metabolized. Therefore, any activity that increases your metabolic rate can help speed up the clearance of nicotine. Nicotine also promotes cancer growth, angiogenesis, and neovascularization. Thereby, nicotine impeding apoptosis, promoting tumor growth and activating growth factors. This article provides a brief description of nicotine is unusual in comparison to most drugs, as its concentration profile changes from induced tumor growth to cytotoxic with increasing doses. The concentration of nicotine stimulated cell growth correspond to low concentration was needed, while high concentration was cytotoxic.
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


National Taipei University of Nursing and Health Sciences, Taiwan
 Jia Ping Wu, Research Center for Healthcare Industry Innovation, National Taipei University of Nursing and
Health Sciences, Taipei City, Taiwan.
To Cite This Article: 
10.34297/AJBSR.2019.05.000872
R August 29, 2019;  September 04, 2019

Tobacco smoking lead to DNA damage. Cigarette smoke con-
tains more than 6,000 components [1]. Smoking is the leading risk
factor for lung cancer. Secondhand smoke exposure or air pollution
appears to be the primary underlying cause of cancer. Exercise is
a good way to increase the rate of metabolism. Exercise improves
heart rate and increases the rate of metabolism and burning of heat
[2]. For people who have many years of smoking, it is important
to start exercising. Make sure to drink plenty of water because
nicotine is soluble in water, so drinking water helps to excrete the
substance through the urine. Vitamin A is also helpful in removing
nicotine from the body because it also has the effect of speeding up
the metabolism [3]. Because nicotine tends to destroy vitamin C in
the body, it is important to supplement it after quitting smoking.
Nicotine is highly addictive. It follows that nicotine is associated
with cancer in humans [4]. Therefore, effects on chemotherapeu-
tics by several malignant cell lines, nicotine in concentrations as
         
    
although a higher nicotine concentration. Nicotine acts as tumor
growth promoted resistance to apoptosis leading to carcinogene-
sis [5]. Nicotine is concomitant dual effects on anti-apoptosis and
genotoxic activity.
Nicotine is unusual in comparison to most drugs. With increas-

high doses it dampens neuronal activity [6]. This phenomenon is
as well-known “Nesbitt’s paradox”. Micronuclei are characterized
in the cancerous cells have some sort of DNA damage. Micronuclei
body is a small body can be seen in a newly divided daughter cell.
Micronuclei body increased is usually an indication of increased
DNA damage or mutation [7]. The mechanisms leading to the for-
mation of Micronuclei body are chromosome breakage and distur-
bance of the chromosome-segregation system, which represents
an irreversible DNA damage. This mechanism responsible for the
genotoxic effects caused by nicotine [8]. Effects of nicotine on an-
giogenesis have been demonstrated for lung tumor cells. Reports
had also been demonstrated in H157 lung cancer, where nicotine
   

consistent cytotoxic effects and appeared to be due to direct cell
kill. Cellular cytotoxicity was associated with inhibition of DNA
synthesis, not stimulation of DNA synthesis. This is the main way
that micronuclei are formed [10]. Micronuclei can also be sponta-
neously formed as a byproduct of inhibition of DNA synthesis. This
mechanism to micronuclei formation is by a double-strand break
DNA, creating a separate linear fragment lead to formation of a mi-
cronucleus. Micronuclei are small [11].
These extranuclear bodies that are formed during mitosis from
lagging chromosomes. This results in parts of the cell senses extra
chromosomes, the cell can attempt to remove the extra chromo-
Copy Right@ Jia Ping Wu
This work is licensed under Creative Commons Attribution 4.0 License
AJBSR.MS.ID.000872.
American Journal of
Biomedical Science & Research
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


Nicotine constitutes approximately 0.6~3.0% of the dry weight of tobacco. Like anything that enters the body, nicotine is also metabolized.
Therefore, any activity that increases your metabolic rate can help speed up the clearance of nicotine. Nicotine also promotes cancer growth,
angiogenesis, and neovascularization. Thereby, nicotine impeding apoptosis, promoting tumor growth and activating growth factors. This article
          
to cytotoxic with increasing doses. The concentration of nicotine stimulated cell growth correspond to low concentration was needed, while high
concentration was cytotoxic.
 Carcinogen; Nicotine; Tumor growth; Cytotoxic; Apoptosis
Am J Biomed Sci & Res Copy@ Jia Ping Wu

48
somes in another cell membrane, separate from the other normal
chromosomes being broken off and enveloped as an extra nucleus
in one of the daughter cells [12]. Nicotine is an important compo-
nent in tobacco. Among various subtypes of nicotinic receptors, ho-
     
and mediate multiple effects of nicotine in lung cancer [13]. nAChRs
expressed on lung carcinoma or mesothelioma form a part of an au-
tocrine-proliferative network facilitating the growth of neoplastic
cells. Target drugs as a form of molecular medicine, targeted ther-
         
targeted molecules needed for carcinogenesis and tumor growth
[14,15]. Nicotine could induce the proliferation of a variety of lung
carcinoma cell clines, but there is no evidence that nicotine itself
provokes cancer. Nicotine alone is generally accepted as a tumor
promoter, but not a tumor initiator in carcinogenesis [16,17]. Nic-
otine can prevent apoptosis induced by various agents in NSCLC.

The concentrations of nicotine promote cell proliferation cor-
respond to the low concentrations, while high concentrations are

activates cell migration, proliferation, survival, and anti-apoptotic
effects exerted, in contract, modulation chemotherapeutics on sev-
eral different malignant cell lines. This phenomenon which nico-
tine-mediated inhibition of apoptosis may contribute to observed
in normal and transformed cells derived from the pathogenesis of
         
cancer therapies.

This work was supported by grants from Ministry of Science
and Technology (MOST 105-2811-B-039-008 and MOST 106-2811-


   -
script.
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-

8. -
sure suppresses fetal adrenal steroidogenesis via steroidogenic factor 1

9. 
Smoking and physical inactivity increase cancer prevalence in BRCA-1
-

10.    
Chronic nicotine exposure mediates resistance to EGFR-TKI in EG-

11.      -
 
2089-2098.
12. Dutra Tavares AC, Silva JO, Nunes Freitas AL, Guimarães VMS, Araújo UC,
-
ward and DOPAC/dopamine ratio in cerebral cortex in adolescent mice,
but does not affect nicotine-induced nAChRs upregulation. Int J Dev

13.          -


14.         
          
1051.
15. -
      

16. Alex I Chernyavsky, Igor B Shchepotin, Valentin Galitovkiy, Sergei A
      
     

17.           -

Pulmonary effects of e-liquid flavors: a systematic review
Article
Full-text available
  • Sep 2022
Electronic cigarettes (ECs) are purported to be tobacco harm-reduction products whose degree of harm has been highly debated. EC use is considered less hazardous than smoking but is not expected to be harmless. Following the banning of e-liquid flavors in countries such as the US, Finland, Ukraine, and Hungary, there are growing concerns regarding the safety profile of e-liquid flavors used in ECs. While these are employed extensively in the food industry and are generally regarded as safe (GRAS) when ingested, GRAS status after inhalation is unclear. The aim of this review was to assess evidence from 38 reports on the adverse effects of flavored e-liquids on the respiratory system in both in vitro and in vivo studies published between 2006 and 2021. Data collected demonstrated greater detrimental effects in vitro with cinnamon (9 articles), strawberry (5 articles), and menthol (10 articles), flavors than other flavors. The most reported effects among these investigations were perturbations of pro-inflammatory biomarkers and enhanced cytotoxicity. There is sufficient evidence to support the toxicological impacts of diacetyl- and cinnamaldehyde-containing e-liquids following human inhalation; however, safety profiles on other flavors are elusive. The latter may result from inconsistencies between experimental approaches and uncertainties due to the contributions from other e-liquid constituents. Further, the relevance of the concentration ranges to human exposure levels is uncertain. Evidence indicates that an adequately controlled and consistent, systematic toxicological investigation of a broad spectrum of e-liquid flavors may be required at biologically relevant concentrations to better inform public health authorities on the risk assessment following exposure to EC flavor ingredients.
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Maternal undernutrition during lactation alters nicotine reward and DOPAC/dopamine ratio in cerebral cortex in adolescent mice, but does not affect nicotine-induced nAChRs upregulation
Article
Full-text available
  • Oct 2017
Early undernutrition causes long lasting alterations that affect the response to psychoactive drugs. Particularly, undernutrition during lactation affects the acute locomotor response to nicotine during adolescence, but the reward effect of continued exposure to nicotine remains unknown. The goal of this study was to investigate the effects of undernutrition during lactation on the nicotine susceptibility indexed via conditioned place preference (CPP), on dopamine content and turnover and on nicotine-induced nicotinic cholinergic receptor (nAChR) upregulation in the cerebral cortex, midbrain and hippocampus of adolescent mice. The impact of undernutrition and nicotine exposure on stress-related hormones and leptin was also investigated. From postnatal day 2 (PN2) to weaning (PN21), dams were randomly assigned to one of the following groups: Control (C) - free access to standard laboratory diet (23% protein); Protein Restricted (PR) - free access to isoenergenetic diet (8% protein); Calorie Restricted (CR) - access to standard laboratory diet in restricted quantities (mean ingestion of PR). PR and CR groups showed less mass gain and less visceral fat mass. While C and CR were equally susceptible to nicotine-induced place preference conditioning, PR failed to show a conditioning pattern. In contrast, all groups presented a nicotine-evoked nAChR upregulation in the cerebral cortex. While dopamine and DOPAC levels did not differ between groups, the DOPAC/dopamine ratio was increased in CR animals. No differences in endocrine parameters were observed. Taken together, our results indicate that undernutrition during lactation programs for brain alterations later in life. Our data also suggest that early undernutrition does not affect the rewarding associative properties of nicotine at adolescence.
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Smoking and physical inactivity increase cancer prevalence in BRCA-1 and BRCA-2 mutation carriers: results from a retrospective observational analysis
Article
Full-text available
  • Dec 2017
  • ARCH GYNECOL OBSTET
Background The aim of this analysis in a pilot study population was to investigate whether we can verify seemingly harmful lifestyle factors such as nicotine and alcohol indulgence, obesity, and physical inactivity, as well as a low socioeconomic status for increased cancer prevalence in a cohort of BRCA 1 and 2 mutation carriers. Methods The analysis data are derived from 68 participants of the lifestyle intervention study LIBRE-1, a randomized, prospective trial that aimed to test the feasibility of a lifestyle modification in BRCA 1 and 2 mutation carriers. At study entry, factors such as medical history, lifestyle behavior, and socioeconomic status were retrospectively documented by interview and the current BMI was determined by clinical examination. The baseline measurements were compared within the cohort, and presented alongside reference values for the German population. ResultsStudy participants indicating a higher physical activity during their adolescence showed a significantly lower cancer prevalence (p = 0.019). A significant difference in cancer occurrence was observed in those who smoked prior to the disease, and those who did not smoke (p < 0.001). Diseased mutation carriers tended to have a lower BMI compared to non-diseased mutation carriers (p = 0.079), whereas non-diseased revealed a significantly higher physical activity level than diseased mutation carriers (p = 0.046). DiscussionThe present data in this small cohort of 68 mutation carriers suggest that smoking and low physical activity during adolescence are risk factors for developing breast cancer in women with BRCA1 or BRCA2 mutation. Further data of the ongoing LIBRE 2 study are necessary to confirm these findings in a larger cohort of 600 mutation carriers.
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Expression patterns for nicotinic acetylcholine receptor subunit genes in smoking-related lung cancers
Article
Full-text available
  • Jul 2017
Cigarette smoking is associated with increased risk for all histologic types of lung cancer, but why the strength of this association is stronger for squamous cell carcinoma than adenocarcinoma of the lung (SQC-L, ADC-L) is not fully understood. Because nicotine and tobacco-specific nitrosamines contribute to carcinogenesis by activating nicotinic acetylcholine receptors (nAChRs) on lung tumors and epithelial cells, we investigated whether differential expression of nAChR subtypes in these tumors could explain their different association with smoking. Expression of nAChR subunit genes in paired tumor and non-tumor lung specimens from 40 SQC-L and 38 ADC-L patients was analyzed by quantitative PCR. Compared to normal lung, both tumors share: i) transcriptional dysregulation of CHRNA3/CHRNA5/CHRNB4 (α3, α5, β4 subunits) at the chromosomal locus that predisposes to lung cancer; and ii) decreased expression of CHRFAM7A (dupα7 subunit); this last subunit negatively modulates α7-nAChR activity in oocytes. In contrast, CHRNA7 (α7 subunit) expression was increased in SQC-L, particularly in smokers and non-survivors, while CHRNA4 (α4 subunit) expression was decreased in ADC-L. Thus, over-representation of cancer-stimulating α7-nAChR in SQC-L, also potentiated by smoking, and under-representation of cancer-inhibiting α4β2-nAChR in ADC-L could explain the different tobacco influences on the tumorigenic process in each cancer type.
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Nicotine induces EP4 receptor expression in lung carcinoma cells by acting on AP-2α: The intersection between cholinergic and prostanoid signaling
Article
Full-text available
  • May 2017
Methods: The non-small cell lung cancer cells of A549 and H1838 were cultured and treated with EP4 inhibitor AH23848, also with EP4 and control siRNAs. The extracellular signal-regulated kinases inhibitor PD98059, the p38 mitogen-activated protein kinase inhibitor SB239063, the α7 nicotinic acetylcholine receptor inhibitor α-bungarotoxin, the α4 nicotinic acetylcholine receptor inhibitor dihydro-β-erythroidine, the PI3K inhibitor wortmannin, the PKC inhibitor calphostin C, and the PKA inhibitor H89 have been used to evaluate the effects on proliferations. It indicates that nicotine increases EP4 expression through α7 nicotinic acetylcholine receptor-dependent activations of PI3-K, JNK and PKC pathways that leads to reduction of AP-2α-DNA binding. This, together with the elevated secretion of PGE2, further enhances the tumor promoting effects of nicotine. These studies suggest a novel molecular mechanism by which nicotine increases non-small cell lung cancer cell proliferation.
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Nicotine Inhibits Cisplatin-Induced Apoptosis via Regulating α5-nAChR/AKT Signaling in Human Gastric Cancer Cells
Article
Full-text available
Gastric cancer incidence demonstrates a strong etiologic association with smoking. Nicotine, the major component in tobacco, is a survival agonist that inhibits apoptosis induced by certain chemotherapeutic agents, but the precise mechanisms involved remain largely unknown. Recently studies have indicated that α5-nicotinic acetylcholine receptor (α5-nAChR) is highly associated with lung cancer risk and nicotine dependence. Nevertheless, no information has been available about whether nicotine also affects proliferation of human gastric cancer cells through regulation of α5-nAChR. To evaluate the hypothesis that α5-nAChR may play a role in gastric cancer, we investigated its expression in gastric cancer tissues and cell lines. The expression of α5-nAChR increased in gastric cancer tissue compared with para-carcinoma tissues. In view of the results, we proceeded to investigate whether nicotine inhibits cisplatin-induced apoptosis via regulating α5-nAChR in gastric cancer cell. The results showed that nicotine significantly promoted cell proliferation in a dose and time-dependent manner through α5-nAChR activation in human gastric cells. Furthermore, nicotine inhibited apoptosis induced by cisplatin. Silence of α5-nAChR ablated the protective effects of nicotine. However, when co-administrating LY294002, an inhibitor of PI3K/AKT pathway, an increased apoptosis was observed. This effect correlated with the induction of Bcl-2, Bax, Survivin and Caspase-3 by nicotine in gastric cell lines. These results suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutic drugs and that α5-nAChR/AKT signaling plays a key role in the anti-apoptotic activity of nicotine induced by cisplatin.
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Mechanisms of tumor-promoting activities of nicotine in lung cancer: Synergistic effects of cell membrane and mitochondrial nicotinic acetylcholine receptors
Article
Full-text available
  • Dec 2015
  • BMC CANCER
One of the major controversies of contemporary medicine is created by an increased consumption of nicotine and growing evidence of its connection to cancer, which urges elucidation of the molecular mechanisms of oncogenic effects of inhaled nicotine. Current research indicates that nicotinergic regulation of cell survival and death is more complex than originally thought, because it involves signals emanating from both cell membrane (cm)- and mitochondrial (mt)-nicotinic acetylcholine receptors (nAChRs). In this study, we elaborated on the novel concept linking cm-nAChRs to growth promotion of lung cancer cells through cooperation with the growth factor signaling, and mt-nAChRs — to inhibition of intrinsic apoptosis through prevention of opening of mitochondrial permeability transition pore (mPTP). Experiments were performed with normal human lobar bronchial epithelial cells, the lung squamous cell carcinoma line SW900, and intact and NNK-transformed immortalized human bronchial cell line BEP2D. We demonstrated that the growth-promoting effect of nicotine mediated by activation of α7 cm-nAChR synergizes mainly with that of epidermal growth factor (EGF), α3 — vascular endothelial growth factor (VEGF), α4 — insulin-like growth factor I (IGF-I) and VEGF, whereas α9 with EGF, IGF-I and VEGF. We also established the ligand-binding abilities of mt-nAChRs and demonstrated that quantity of the mt-nAChRs coupled to inhibition of mPTP opening increases upon malignant transformation. These results indicated that the biological sum of simultaneous activation of cm- and mt-nAChRs produces a combination of growth-promoting and anti-apoptotic signals that implement the tumor-promoting action of nicotine on lung cells. Therefore, nAChRs may be a promising molecular target to arrest lung cancer progression and re-open mitochondrial apoptotic pathways.
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Nicotine Augments the Beneficial Effects of Mesenchymal Stem Cell-based Therapy in Rat Model of Multiple Sclerosis
Article
  • Nov 2017
Experimental autoimmune encephalomyelitis (EAE) in rats through immunization with guinea pig spinal cord homogenate (GPSCH) produces a chronic disease with a relapsing pattern such as multiple sclerosis (MS) in humans. In previous studies, the immunomodulatory benefits of mesenchymal stem cells (MSCs) and nicotine have already been determined. Thus, this research was conducted to assess the additional benefits of the combination therapy of MSCs and nicotine in a rat model of MS. EAE was induced by GPSCH and complete Freund’s adjuvant (CFA) in female Wistar rats. The therapies were initiated at day 12 post-immunization (p.i.), when the rats developed a neurological disability score. The symptoms were recorded daily until day 33, when the rats were sacrificed. Finally, the splenocytes were evaluated by Enzyme-linked immunosorbent assay (ELISA) for cytokine production. The therapeutic treatment in the EAE rats with a combination of MSCs and nicotine exhibited a more desirable outcome, causing the regression of the average mean clinical score and neuropathological features to be more favorable than the treatment with either therapy alone. The combination therapy led to a significant reduction in the cumulative disease disability from day 21. For the EAE rats treated with nicotine and MSCs, this period was started from day 22 and 28 p.i., respectively. Besides the increase in the levels of IL-10, the combined therapy significantly reduced the splenocytes production of pro-inflammatory IL-17 as well as TNF-α more profoundly than either of the medications alone. In conclusion, the combination of MSCs and nicotine can be suggested as a promising strategy for further MS therapeutics improvement.
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How Intravenous Nicotine Administration in Smokers Can Inform Tobacco Regulatory Science
Article
  • Oct 2016
Objectives: Reducing the negative health effects caused by tobacco products continues to be a public health priority. The Family Smoking Prevention and Tobacco Control Act of 2009 gave the Food Drug Administration authority to pursue several new strategies, including regulating levels of nicotine and other ingredients in tobacco products. A nicotine reduction strategy proposed by Benowitz and Henningfield may reduce the nicotine content of tobacco products to an amount below a threshold that supports neither the development nor maintenance of addiction. However, many factors must be considered to determine the viability and efficacy of this approach. For example, the policy should be based on precise information on the dose-dependent effects of nicotine on reinforcement and factors that contribute to individual differences in these effects. To date there have been few studies on these topics in humans. Methods: We review nicotine pharmacology and reinforcement then present several studies illustrating the application of intravenous (IV) nicotine delivery to study nicotine reinforcement in humans. Results: Nicotine delivery by IV infusion may be uniquely suited for studying nicotine's dose-dependent effects. Conclusion: This procedure can inform tobacco regulatory science to facilitate the development of effective tobacco control policies.
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Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal
Article
  • Feb 2015
  • LUNG CANCER
Some of patients with non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) show poor responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment. Cigarette smoking is the strongest documented risk factor for the development of lung cancer. Nicotine, while not carcinogenic by itself, has been shown to induce proliferation, angiogenesis, and the epithelial-mesenchymal transition; these effects might be associated with EGFR-TKI resistance. PC-9 and 11_18 cell lines (EGFR-mutated NSCLC cell lines) were cultured with 1μM nicotine for 3 months and were designated as PC-9/N and 11_18/N cell lines, respectively. The sensitivities of these cell lines to EGFR-TKI were then tested in vitro. Moreover, the association between the smoking status and the progression-free survival (PFS) period was investigated in patients with EGFR-mutated NSCLC who were treated with gefitinib. The PC-9/N and 11_18/N cell lines were resistant to EGFR-TKI, compared with controls. The phosphorylation of EGFR in these cell lines was reduced by EGFR-TKI to a smaller extent than that observed in controls, and a higher concentration of EGFR-TKI was capable of further decreasing the phosphorylation. Clinically, smoking history was an independent predictor of a poor PFS period on gefitinib treatment. Chronic nicotine exposure because of cigarette smoking mediates resistance to EGFR-TKI via an EGFR signal. Smoking cessation is of great importance, while resistance may be overcome through the administration of high-dose EGFR-TKI. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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Prenatal nicotinic exposure suppresses fetal adrenal steroidogenesis via steroidogenic factor 1 (SF-1) deacetylation
Article
  • Apr 2014
  • TOXICOL APPL PHARM
This study aimed to investigate the suppressive effect of nicotine on fetal adrenal steroidogenesis and to explore the potential role of epigenetic modification of steroidogenic factor-1 (SF-1) transcriptional activity in this process. Nicotine was intragastrically administered to pregnant rats and NCI-H295A cells were treated with nicotine or trichostatin A (TSA). The pathomorphology of fetal adrenals, steroid hormones levels, the expression of SF-1 and its target genes, histone deacetylases (HDACs) mRNA were analyzed. Histone modification and DNA methylation of the SF-1 promoter region were assessed using chromatin immunoprecipitation (ChIP) and bisulfite sequencing PCR. The interaction between SF1 and its target genes were observed. Prenatal nicotinic exposure decreased fetal body weight, increased the IUGR rate and caused detrimental changes in fetal adrenal. In addition, the levels of corticosterone, the expression of SF-1 and its target genes were decreased while HDAC2 expression was enhanced. Nicotine treatment decreased histone H3K9 and H3K14 acetylation levels while there was no nicotinic effect on the methylation frequency on the SF-1 promoter region. Furthermore, in nicotine-treated NCI-H295A cells, lower levels of steroidogenic synthesis, lower expression of SF-1 and its target genes were observed while the expression of HDACs was enhanced. The interaction between SF1 and StAR decreased with nicotine treatment. Nicotine treatment decreased histone H3K9 and H3K14 acetylation levels, and addition of TSA reversed the inhibition of nicotine-mediated SF-1 and its partial target genes. Thus, nicotine-mediated reduction of SF-1 expression resulted in an inhibitory effect on the expression of its target genes and steroid production via histone deacetylation.
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