β2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway
Open accessAbstract
Background: Smoking and stress, pancreatic cancer (PanCa) risk factors, stimulate nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and catecholamines production respectively. NNK and catecholamine bind the β-adrenoceptors and induce PanCa cell proliferation; and we have previously suggested that β-adrenergic antagonists may suppress proliferation and invasion and stimulate apoptosis in PanCa. To clarify the mechanism of apoptosis induced by β 2-adrenergic antagonist, we hypothesize that blockage of the β 2-adrenoceptor could induce G 1/S phase arrest and apoptosis and Ras may be a key player in PanCa cells. Results: The β 1 and β 2-adrenoceptor proteins were detected on the cell surface of PanCa cells from pancreatic carcinoma specimen samples by immunohistochemistry. The β 2-adrenergic antagonist ICI118,551 significantly induced G 1/S phase arrest and apoptosis compared with the β 1-adrenergic antagonist metoprolol, which was determined by the flow cytometry assay. β 2-adrenergic antagonist therapy significantly suppressed the expression of extracellular signal-regulated kinase, Akt, Bcl-2, cyclin D1, and cyclin E and induced the activation of caspase-3, caspase-9 and Bax by Western blotting. Additionally, the β 2-adrenergic antagonist reduced the activation of NFκB in vitro cultured PanCa cells. Conclusions: The blockage of β 2-adrenoceptor markedly induced PanCa cells to arrest at G 1/S phase and consequently resulted in cell death, which is possibly due to that the blockage of β 2-adrenoceptor inhibited NFκB, extracellular signal-regulated kinase, and Akt pathways. Therefore, their upstream molecule Ras may be a key factor in the β 2-adrenoceptor antagonist induced G 1/S phase arrest and apoptosis in PanCa cells. The new pathway discovered in this study may provide an effective therapeutic strategy for PanCa.
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Blocking β2-ARs induces G1/S phase arrest and apoptosis in pancreatic cancer cells via the Ras/Akt/NFκB pathway.
“Zhang et al. (41) found that by blocking the β2-ARs, a G1/S phase arrest and apoptosis could be induced in pancreatic cancer cells via the Ras/Akt/NFκB pathway.”
From Chronic Stress Promotes Cancer Development (2020) · cites this paper as [41]
The Discussion reports that β2-adrenoceptor antagonism induced G1/S arrest and apoptosis in pancreatic cancer cells and links these effects to Akt and NF-κB signaling. It says only that K-ras *may* be a key molecule, so the claim presents Ras’s role in the pathway more definitively than the paper does. Page numbers are unavailable in our copy. (LLM, conf=0.83)
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Cites
Hidalgo, M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0901557 · Cited by 2,570 · see citing works
Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma
Thaker, P. H., Han, L. Y., Kamat, A. A., Arevalo, J. M., Takahashi, R., Lu, C., Jennings, N. B., Armaiz-Pena, G., Bankson, J. A., Ravoori, M., et al. (2006) · Nature Medicine · doi:10.1038/nm1447 · Cited by 1,320 · see citing works
The influence of bio-behavioural factors on tumour biology: pathways and mechanisms
Antoni, M. H., Lutgendorf, S. K., Cole, S. W., Dhabhar, F. S., Sephton, S. E., McDonald, P. G., Stefanek, M., & Sood, A. K. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1820 · Cited by 981 · see citing works
Flagged first, then by citations
Research works printed but not linked: 27
- Jemal A Siegel R Ward E Hao Y Xu J Thun MJ Cancer statistics, 2009 CA Cancer J Clin 2009 59 225 249 10.3322/caac.20006 19474385 · DOI · Paper page
- Raimondi S Maisonneuve P Lowenfels AB Epidemiology of pancreatic cancer: an overview Nat Rev Gastroenterol Hepatol 2009 6 699 708 10.1038/nrgastro.2009.177 19806144 · DOI
- Al-Wadei HA Schuller HM Nicotinic receptor-associated modulation of stimulatory and inhibitory neurotransmitters in NNK-induced adenocarcinoma of the lungs and pancreas J Pathol 2009 218 437 445 10.1002/path.2542 19274673 PMC3372983 · DOI
- Davis R Rizwani W Banerjee S Kovacs M Haura E Coppola D Chellappan S Nicotine promotes tumor growth and metastasis in mouse models of lung cancer PLoS One 2009 4 e7524 10.1371/journal.pone.0007524 19841737 PMC2759510 · DOI
- Sood AK Bhatty R Kamat AA Landen CN Han L Thaker PH Li Y Gershenson DM Lutgendorf S Cole SW Stress hormone-mediated invasion of ovarian cancer cells Clin Cancer Res 2006 2 369 375 PMC3141061 16428474
- Wu WK Wong HP Luo SW Chan K Huang FY Hui MK Lam EK Shin VY Ye YN Yang YH Cho CH 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone from cigarette smoke stimulates colon cancer growth via beta-adrenoceptors Cancer Res 2005 65 5272 5277 10.1158/0008-5472.CAN-05-0205 15958573 · DOI
- Schuller HM Neurotransmission and cancer: implications for prevention and therapy Anticancer Drugs 2008 19 655 671 10.1097/CAD.0b013e3283025b58 18594207 · DOI
- McGraw DW Liggett SB Molecular mechanisms of β2-adrenergic receptor function and regulation Proc Am Thorac Soc 2005 2 292 296 10.1513/pats.200504-027SR 16267351 PMC2713324 · DOI
- Schuller HM Al-Wadei HA Neurotransmitter receptors as central regulators of pancreatic cancer Future Oncol 2010 6 221 228 10.2217/fon.09.171 20146581 PMC2832917 · DOI
- Weddle DL Tithoff P Williams M Schuller HM Beta-adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas Carcinogenesis 2001 22 473 479 10.1093/carcin/22.3.473 11238189 · DOI
- Zhang D Ma QY Hu HT Zhang M Beta2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NF-kappaB and AP-1 Cancer Biol Ther 2010 10 19 29 10.4161/cbt.10.1.11944 20424515 · DOI
- Schuller HM Mechanisms of smoking-related lung and pancreatic adenocarcinoma development Nat Rev Cancer 2002 2 455 463 10.1038/nrc824 12189387 · DOI
- Askari MD Tsao MS Schuller HM The tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through beta-adrenergic transactivation of EGF receptors J Cancer Res Clin Oncol 2005 131 639 648 10.1007/s00432-005-0002-7 16091975 PMC12161179 · DOI
- McCubrey JA Steelman LS Chappell WH Abrams SL Wong EW Chang F Lehmann B David TM Michele M Agostino T Franca S Massimo L Jorg B Camilla E Alberto MM Richard AF Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance Biochim Biophys Acta 2007 1773 1263 1284 10.1016/j.bbamcr.2006.10.001 17126425 PMC2696318 · DOI
- Majidi M Al-Wadei HA Takahashi T Schuller HM Nongenomic beta estrogen receptors enhance beta1 adrenergic signaling induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human small airway epithelial cells Cancer Res 2007 67 6863 6871 10.1158/0008-5472.CAN-07-0483 17638897 · DOI
- Vargiu P De Abajo R Garcia-Ranea JA Valencia A Santisteban P Crespo P Bernal J The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors Oncogene 2004 23 559 568 14724584
- Luttrell LM Ferguson SS Daaka Y Miller WE Maudsley S Della Rocca GJ Lin FT Kawakatsu H Owada K Luttrell DK Caron MG Lefkowitz RJ β-Arrestin-dependent formation of β2 adrenergic receptor-src protein kinase complexes Science 1999 283 655 661 10.1126/science.283.5402.655 9924018 · DOI
- Hirsch E Ciraolo E Ghigo A Costa C Taming the PI3K team to hold inflammation and cancer at bay Pharmacol Therapeut 2008 118 192 205 10.1016/j.pharmthera.2008.02.004 18420279 · DOI
- Zhang D Ma Q Shen S Hu H Inhibition of pancreatic cancer cell proliferation by propranolol occurs through apoptosis induction: the study of beta-adrenoceptor antagonist's anticancer effect in pancreatic cancer cell Pancreas 2009 38 94 100 10.1097/MPA.0b013e318184f50c 19106745 · DOI
- Hu HT Ma QY Zhang D Shen SG Han L Ma YD Li RF Xie KP HIF-1alpha links beta-adrenoceptor agonists and pancreatic cancer cells under normoxic condition Acta Pharmacol Sin 2010 31 102 110 10.1038/aps.2009.181 20037603 PMC4002695 · DOI
- Gardner-Thorpe J Ito H Ashley SW Whang EE Differential display of expressed genes in pancreatic cancer cells Biochem Biophys Res Commun 2002 293 391 395 10.1016/S0006-291X(02)00237-1 12054612 · DOI
- Chen ZB Liu C Chen FQ Li SY Liang Q Liu LY Effects of tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on the activation of ERK1/2 MAP kinases and the proliferation of human mammary epithelial cells Environ Toxicol Pharmacol 2006 22 283 291 10.1016/j.etap.2006.04.001 21783722 · DOI
- Foster I Cancer: A cell cycle defect Radiography 2008 14 144 149 10.1016/j.radi.2006.12.001 · DOI
- Leicht DT Balan V Kaplun A Singh-Gupta V Kaplun L Dobson M Guri T Raf kinases: Function, regulation and role in human cancer Biochim Biophys Acta 2007 1773 1196 1212 10.1016/j.bbamcr.2007.05.001 17555829 PMC1986673 · DOI
- Weyden L Adams DJ The Ras-association domain family (RASSF) members and their role in human tumourigenesis Biochim Biophys Acta 2007 1776 58 85 17692468 PMC2586335
- Chambard JC Lefloch R Pouysségur J Lenormand P ERK implication in cell cycle regulation Biochim Biophys Acta 2007 1773 1299 1310 10.1016/j.bbamcr.2006.11.010 17188374 · DOI
- Herr I Debatin KM Cellular stress response and apoptosis in cancer therapy Blood 2001 98 2603 2614 10.1182/blood.V98.9.2603 11675328 · DOI
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Chronic Stress Promotes Cancer Development
Dai, S., Mo, Y., Wang, Y., Xiang, B., Liao, Q., Zhou, M., Li, X., Li, Y., Xiong, W., Li, G., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01492 · Cited by 405 · see citing works
Gosain, R., Gage-Bouchard, E., Ambrosone, C., Repasky, E., & Gandhi, S. (2020) · Seminars in Immunopathology · doi:10.1007/s00281-020-00815-y · Cited by 85 · see citing works
Pellegata, N. S., Berriel Diaz, M., Rohm, M., & Herzig, S. (2022) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10058-y · Cited by 33 · see citing works
- Authors
- Zhang, D., Ma, Q., Wang, Z., Zhang, M., Guo, K., Wang, F., & Wu, E.
- Affiliations
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- North Dakota State University (US)
- Corresponding author
- Ma, Qingyong
- Wu, Erxi
- Venue
- Molecular Cancer
- Published
- 2011-11-26
- Volume
- 10
- Issue
- 1
- Pages
- 146-146
- ISSN
- 1476-4598 (ISSN-L)
- PMC
- PMC3250953
- OpenAlex
- W2102717686
- Cited by
- 106
- References
- 3
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 9 · 2023: 8 · 2022: 13 · 2021: 5 · 2020: 10 · 2019: 8 · 2018: 9 · 2017: 4 · 2016: 3 · 2015: 13 · 2014: 7 · 2012: 3
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Cancer (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81172360)
- National Institutes of Health (2p20rr020151-06a1, P20-RR-020-151, NIH P20 RR020151)
- National Center for Research Resources (P20-RR-020-151)
- Office of Experimental Program to Stimulate Competitive Research
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- beta2-adrenergic receptor, beta-blockers, pancreatic cancer, apoptosis, G1/S cell cycle arrest, NF-κB, ERK, caspase activation, Bcl-2, cyclin D1, cyclin E, metoprolol, catecholamines, NNK
- MeSH terms
- Animals, Humans, Mice, Inbred BALB C, Mice, Nude, Pancreatic Neoplasms, Receptors, Adrenergic, beta, Signal Transduction, G1 Phase, S Phase, NF-kappa B, Apoptosis, ras Proteins, Proto-Oncogene Proteins c-akt, Mice, Adrenergic beta-2 Receptor Antagonists
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