β2-adrenergic receptor activation promotes the proliferation of A549 lung cancer cells via the ERK1/2/CREB pathway

Hu,Ping; He,Jingjing; Liu,Shiling; Wang,Meng; Pan,Bingxing; Zhang,Wenhua

doi:10.3892/or.2016.4966

β2-adrenergic receptor activation promotes the proliferation of A549 lung cancer cells via the ERK1/2/CREB pathway

Authors:
- Ping Hu
- Jingjing He
- Shiling Liu
- Meng Wang
- Bingxing Pan
- Wenhua Zhang
View Affiliations

Affiliations: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330001, P.R. China, Institute of Life Science, Nanchang University, Nanchang, Jiangxi 330001, P.R. China
Published online on: July 22, 2016 https://doi.org/10.3892/or.2016.4966
Pages: 1757-1763

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Lung cancer is one of the most common cancers worldwide and accounts for 28% of all cancer-related deaths. The expression of the β2‑adrenergic receptor (β2‑AR), one of the stress‑inducible receptors, has been reported to be closely correlated with malignant tumors. However, the role of β2‑AR activation in human lung epithelial‑derived cancer A549 cells and the underlying mechanisms are not fully understood. In the present study, we found that activation of β2‑AR but not β1‑AR promoted the proliferation of A549 cells. Isoproterenol (ISO) stimulation of β2‑AR induced extracellular signal‑regulated kinase 1/2 (ERK1/2) and cyclic adenosine monophosphate response element‑binding protein (CREB) phosphorylation. Blocking the ERK1/2 pathway by U0126 inhibited CREB phosphorylation and also suppressed A549 cell proliferation. Moreover, ISO treatment enhanced the expression of matrix metalloproteinase (MMP) family proteins such as MMP‑2, MMP‑9, and also vascular endothelial growth factor (VEGF), which were able to be blocked by knockdown of CREB. In conclusion, our data revealed that β2‑AR induced ERK1/2 phosphorylation which in turn activated CREB to promote A549 cell proliferation. These findings elucidate potential therapeutic targets for lung cancer treatment.

View Figures

View References

1	Kelly A, Blair N and Pechacek TF: Women and smoking: Issues and opportunities. J Womens Health Gend Based Med. 10:515–518. 2001. View Article : Google Scholar : PubMed/NCBI
2	Dela Cruz CS, Tanoue LT and Matthay RA: Lung cancer: Epidemiology, etiology, and prevention. Clin Chest Med. 32:605–644. 2011. View Article : Google Scholar : PubMed/NCBI
3	Sakashita S, Sakashita M and Sound Tsao M: Genes and pathology of non-small cell lung carcinoma. Semin Oncol. 41:28–39. 2014. View Article : Google Scholar : PubMed/NCBI
4	Wakelee HA, Chang ET, Gomez SL, Keegan TH, Feskanich D, Clarke CA, Holmberg L, Yong LC, Kolonel LN, Gould MK, et al: Lung cancer incidence in never smokers. J Clin Oncol. 25:472–478. 2007. View Article : Google Scholar : PubMed/NCBI
5	Yano T, Haro A, Shikada Y, Maruyama R and Maehara Y: Non-small cell lung cancer in never smokers as a representative 'non-smoking-associated lung cancer': Epidemiology and clinical features. Int J Clin Oncol. 16:287–293. 2011. View Article : Google Scholar : PubMed/NCBI
6	Robinson JD and Cinciripini PM: The effects of stress and smoking on catecholaminergic and cardiovascular response. Behav Med. 32:13–18. 2006. View Article : Google Scholar : PubMed/NCBI
7	Timmermans W, Xiong H, Hoogenraad CC and Krugers HJ: Stress and excitatory synapses: From health to disease. Neuroscience. 248:626–636. 2013. View Article : Google Scholar : PubMed/NCBI
8	Cole SW and Sood AK: Molecular pathways: Beta-adrenergic signaling in cancer. Clin Cancer Res. 18:1201–1206. 2012. View Article : Google Scholar :
9	Schuller HM and Al-Wadei HAN: Neurotransmitter receptors as central regulators of pancreatic cancer. Future Oncol. 6:221–228. 2010. View Article : Google Scholar : PubMed/NCBI
10	Audet M and Bouvier M: Insights into signaling from the beta2-adrenergic receptor structure. Nat Chem Biol. 4:397–403. 2008. View Article : Google Scholar : PubMed/NCBI
11	Laag E, Majidi M, Cekanova M, Masi T, Takahashi T and Schuller HM: NNK activates ERK1/2 and CREB/ATF-1 via beta-1-AR and EGFR signaling in human lung adenocarcinoma and small airway epithelial cells. Int J Cancer. 119:1547–1552. 2006. View Article : Google Scholar : PubMed/NCBI
12	Schuller HM and Cekanova M: NNK-induced hamster lung adenocarcinomas over-express beta2-adrenergic and EGFR signaling pathways. Lung Cancer. 49:35–45. 2005. View Article : Google Scholar : PubMed/NCBI
13	Zhang W, Xu C, Tu H, Wang Y, Sun Q, Hu P, Hu Y, Rondard P and Liu J: GABAB receptor upregulates fragile X mental retardation protein expression in neurons. Sci Rep. 5:104682015. View Article : Google Scholar : PubMed/NCBI
14	Deryugina EI and Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25:9–34. 2006. View Article : Google Scholar : PubMed/NCBI
15	Entschladen F, Drell TL IV, Lang K, Joseph J and Zaenker KS: Tumour-cell migration, invasion, and metastasis: Navigation by neurotransmitters. Lancet Oncol. 5:254–258. 2004. View Article : Google Scholar : PubMed/NCBI
16	Al-Wadei HA, Takahashi T and Schuller HM: Caffeine stimulates the proliferation of human lung adenocarcinoma cells and small airway epithelial cells via activation of PKA, CREB and ERK1/2. Oncol Rep. 15:431–435. 2006.PubMed/NCBI
17	Palm D, Lang K, Niggemann B, Drell TL IV, Masur K, Zaenker KS and Entschladen F: The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers. Int J Cancer. 118:2744–2749. 2006. View Article : Google Scholar
18	Drell TL IV, Joseph J, Lang K, Niggemann B, Zaenker KS and Entschladen F: Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat. 80:63–70. 2003. View Article : Google Scholar : PubMed/NCBI
19	Sood AK, Bhatty R, Kamat AA, Landen CN, Han L, Thaker PH, Li Y, Gershenson DM, Lutgendorf S and Cole SW: Stress hormone-mediated invasion of ovarian cancer cells. Clin Cancer Res. 12:369–375. 2006. View Article : Google Scholar : PubMed/NCBI
20	Mersmann HJ: Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action. J Anim Sci. 76:160–172. 1998.PubMed/NCBI
21	Yuan A, Li Z, Li X, Yi S, Wang S, Cai Y and Cao H: The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells. Oncol Rep. 23:151–157. 2010.
22	Bevilacqua M, Norbiato G, Chebat E, Baldi G, Bertora P, Regalia E, Colella G, Gennari L and Vago T: Changes in alpha-1 and beta-2 adrenoceptor density in human hepatocellular carcinoma. Cancer. 67:2543–2551. 1991. View Article : Google Scholar : PubMed/NCBI
23	Kassahun WT, Guenl B, Ungemach FR, Jonas S and Abraham G: Expression and functional coupling of liver β₂-adrenoceptors in the human hepatocellular carcinoma. Pharmacology. 89:313–320. 2012. View Article : Google Scholar
24	Schuller HM, Tithof PK, Williams M and Plummer H III: The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a beta-adrenergic agonist and stimulates DNA synthesis in lung adenocarcinoma via beta-adrenergic receptor-mediated release of arachidonic acid. Cancer Res. 59:4510–4515. 1999.PubMed/NCBI
25	Pradidarcheep W, Stallen J, Labruyère WT, Dabhoiwala NF, Michel MC and Lamers WH: Lack of specificity of commercially available antisera against muscarinergic and adrenergic receptors. Naunyn Schmiedebergs Arch Pharmacol. 379:397–402. 2009. View Article : Google Scholar : PubMed/NCBI
26	Daly CJ and McGrath JC: Previously unsuspected widespread cellular and tissue distribution of β-adrenoceptors and its relevance to drug action. Trends Pharmacol Sci. 32:219–226. 2011. View Article : Google Scholar : PubMed/NCBI
27	Shenoy SK and Lefkowitz RJ: β-arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol Sci. 32:521–533. 2011. View Article : Google Scholar : PubMed/NCBI
28	Sun Y, McGarrigle D and Huang X-Y: When a G protein-coupled receptor does not couple to a G protein. Mol Biosyst. 3:849–854. 2007. View Article : Google Scholar : PubMed/NCBI
29	Egeblad M and Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2:161–174. 2002. View Article : Google Scholar : PubMed/NCBI
30	Fingleton B: Matrix metalloproteinases: Roles in cancer and metastasis. Front Biosci. 11:479–491. 2006. View Article : Google Scholar
31	Curran S and Murray GI: Matrix metalloproteinases: Molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer. 36:1621–1630. 2000. View Article : Google Scholar : PubMed/NCBI
32	Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J, Jabbari S, Rainwater K, Ritchie JM, Yang M and Sood AK: Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin Cancer Res. 9:4514–4521. 2003.PubMed/NCBI