Nicotine Induces Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor by α1 Nicotinic Acetylcholine Receptor–Mediated Activation in.

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Nicotine Induces Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor by α1 Nicotinic Acetylcholine Receptor–Mediated Activation in PC9 Cells Shuo Wang, MD, Koichi Takayama, MD, PhD, Kentaro Tanaka, MD, PhD, Masafumi Takeshita, MD, PhD, Noriaki Nakagaki, MD, PhD, Kayo Ijichi, MD, Heyan Li, MD, Yoichi Nakanishi, MD, PhD Journal of Thoracic Oncology Volume 8, Issue 6, Pages 719-725 (June 2013) DOI: 10.1097/JTO.0b013e31828b51d4 Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 A, NSCLC cell lines express nAChR mRNA and protein. Detection of reverse-transcriptase polymerase chain reaction products for α1 nAChR subunits in A549, H2122, and PC9 cell lines. The BEAS 2B cell line was a positive control. Products were sequenced and in each case confirmed to be the expected authentic sequence for each subunit. M, 100 bp molecular marker with the brightest band at 600 bp. B, Western blot results for α1 nAChR subunits. NSCLC cell lines express nAChR protein. BEAS 2B cell line or HEK293 cell line served as the positive or negative control, respectively. nAChR, nicotine acetylcholine receptors; NSCLC, non–small-cell lung cancer. Journal of Thoracic Oncology 2013 8, 719-725DOI: (10.1097/JTO.0b013e31828b51d4) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Representative photographs of tissue microarrays showing that non–small-cell lung cancer tissue expressed α1 nicotine acetylcholine receptors. Dark-brown staining was indicative of the presence of α1 protein, and tissue was counterstained to indicate nuclei with dark-blue staining. A, adenocarcinoma ×400; (B), squamous cell carcinoma ×400; (C), large-cell carcinoma ×400; and (D), small-cell carcinoma ×400. Journal of Thoracic Oncology 2013 8, 719-725DOI: (10.1097/JTO.0b013e31828b51d4) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 A, Induction of Erk, Akt (Ser-473) and STAT3 phosphorylation by nicotine. PC9 cells were serum-starved for 24 hours then incubated with 10 µM of nicotine for the number of times indicated (upper panel). Western blot analysis was used to reveal the time-dependent phosphorylation of ERK and Akt (Ser-473); (B) Induction of Erk and Akt (Ser-473) phosphorylation was dependent on α1 nAChR. PC9 cells were transfected with siRNA against α1 nAChR subunit (si-α1) or NT siRNA for 72 hours. Western blot analysis revealed the difference in phosphorylated levels of ERK1/2 (p-ERK1/2) and Akt (p-Akt) between cells treated with siRNA α1 and NT; (C) Induction of EFGR phosphorylation by nicotine. PC9 cells were serum-starved for 24 hours then incubated with 10 µM of nicotine for the number of times indicated (upper panel). Western blot analysis shows the EGFR and p-EGFR protein levels; (D) Role of α1 nAChR subunit in the EFGR signaling pathway. PC9 cells were transfected with siRNA against the α1 nAChR subunits (si-α1) or NT siRNA for 72 hours. Western blot analysis shows EGFR and p-EGFR protein levels. EFGR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; nAChR, nicotinic acetylcholine receptor; NT, nontargeting. Journal of Thoracic Oncology 2013 8, 719-725DOI: (10.1097/JTO.0b013e31828b51d4) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 A, Gene silencing of α1 nAChR was validated by reverse transcription PCR in PC9 cells. α1 nAChR mRNA expression was knocked down by siRNA; (B) The relative levels of α1 nAChR mRNA measured by real-time-PCR in control NT and α1 nAChR knockdown (si-α1) PC9 cells. Data are presented as mean ± standard error mean of three independent experiments carried out in triplicate. *p < 0.05. nAChR, nicotinic acetylcholine receptor; NT, nontargeting; PCR, polymerase chain reaction. Journal of Thoracic Oncology 2013 8, 719-725DOI: (10.1097/JTO.0b013e31828b51d4) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 A, Nicotine protects NSCLC cells from cytotoxicity induced by EGFR-TKI. NSCLC PC9 cells were pretreated with 1 µM of nicotine for 1 month or 10 µM of nicotine for 1 day. Cells were then treated with EGFR-TKI for 48 hours. Cell survival was measured with the MTS assay and was expressed as a percentage of the untreated control. The concentrations of EGFR-TKI were increased in increments as indicated. Data are presented as mean ± standard error mean of three independent experiments carried out in triplicate. *p < 0.05; **p < 0.01; ***p < 0.001. B, α1 nAChR subunit mediated EGFR-TKI resistance induced by long-term nicotine exposure. PC9 cells were pretreated with 1µM of nicotine for 1 month, then transfected with siRNA against α1 nAChR subunit (si-α1) or nontargeting siRNA NT for 72 hours. Cell survival was measured with the MTS assay and is expressed as a percentage of the untreated control. The concentrations of EGFR-TKI were increased in increments as indicated. Data are presented as mean ± standard error mean of three independent experiments carried out in triplicate. *p < 0.05; **p < 0.01; ***p < 0.001. EFGR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; NSCLC, non–small-cell lung cancer; NT, nontargeting. Journal of Thoracic Oncology 2013 8, 719-725DOI: (10.1097/JTO.0b013e31828b51d4) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions