Asperolide A, a marine-derived tetranorditerpenoid, induces G2/M arrest in human NCI-H460 lung carcinoma cells, is mediated by p53-p21 stabilization and modulated by Ras/Raf/MEK/ERK signaling pathway
- PMID: 23434831
- PMCID: PMC3640382
- DOI: 10.3390/md11020316
Asperolide A, a marine-derived tetranorditerpenoid, induces G2/M arrest in human NCI-H460 lung carcinoma cells, is mediated by p53-p21 stabilization and modulated by Ras/Raf/MEK/ERK signaling pathway
Abstract
Here we first demonstrate that asperolide A, a very recently reported marine-derived tetranorditerpenoid, leads to the inhibition of NCI-H460 lung carcinoma cell proliferation by G2/M arrest with the activation of the Ras/Raf/MEK/ERK signaling and p53-dependent p21 pathway. Treatment with 35 μM asperolide A (2 × IC(50)) resulted in a significant increase in the proportion of G2/M phase cells, about a 2.9-fold increase during 48 h. Immunoblot assays demonstrated time-dependent inhibition of G2/M regulatory proteins. Moreover, asperolide A significantly activated MAP kinases (ERK1/2, JNK and p38 MAP kinase) by phosphorylation, and only the inhibition of ERK activation by PD98059 reversed downregulation of G2/M regulatory proteins CDC2, and suppressed upregulation of p21 and p-p53 levels. Transfection of cells with dominant-negative Ras (RasN17) mutant genes up-regulated asperolide A-induced the decrease of cyclin B1 and CDC2, suppressed Raf, ERK activity and p53-p21 expression, and at last, abolished G2/M arrest. This study indicates that asperolide A-induced G2/M arrest in human NCI-H460 lung carcinoma cells relys on the participation of the Ras/Raf/MEK/ERK signaling pathway in p53-p21 stabilization. An in vivo study with asperolide A illustrated a marked inhibition of tumor growth, and little toxcity compared to Cisplatin therapy. Overall, these findings provide potential effectiveness and a theoretical basis for the therapeutic use of asperolide A in the treatment of malignancies.
Figures
Similar articles
-
Wentilactone A as a novel potential antitumor agent induces apoptosis and G2/M arrest of human lung carcinoma cells, and is mediated by HRas-GTP accumulation to excessively activate the Ras/Raf/ERK/p53-p21 pathway.Cell Death Dis. 2013 Dec 5;4(12):e952. doi: 10.1038/cddis.2013.484. Cell Death Dis. 2013. PMID: 24309939 Free PMC article.
-
Wentilactone B induces G2/M phase arrest and apoptosis via the Ras/Raf/MAPK signaling pathway in human hepatoma SMMC-7721 cells.Cell Death Dis. 2013 Jun 6;4(6):e657. doi: 10.1038/cddis.2013.182. Cell Death Dis. 2013. PMID: 23744357 Free PMC article.
-
Oridonin induces G2/M arrest and apoptosis via activating ERK-p53 apoptotic pathway and inhibiting PTK-Ras-Raf-JNK survival pathway in murine fibrosarcoma L929 cells.Arch Biochem Biophys. 2009 Oct 1;490(1):70-5. doi: 10.1016/j.abb.2009.08.011. Epub 2009 Aug 20. Arch Biochem Biophys. 2009. PMID: 19699177
-
Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance.Biochim Biophys Acta. 2007 Aug;1773(8):1263-84. doi: 10.1016/j.bbamcr.2006.10.001. Epub 2006 Oct 7. Biochim Biophys Acta. 2007. PMID: 17126425 Free PMC article. Review.
-
Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy.Leukemia. 2011 Jul;25(7):1080-94. doi: 10.1038/leu.2011.66. Epub 2011 Apr 15. Leukemia. 2011. PMID: 21494257 Review.
Cited by
-
Wentilactone A as a novel potential antitumor agent induces apoptosis and G2/M arrest of human lung carcinoma cells, and is mediated by HRas-GTP accumulation to excessively activate the Ras/Raf/ERK/p53-p21 pathway.Cell Death Dis. 2013 Dec 5;4(12):e952. doi: 10.1038/cddis.2013.484. Cell Death Dis. 2013. PMID: 24309939 Free PMC article.
-
Mertensene, a Halogenated Monoterpene, Induces G2/M Cell Cycle Arrest and Caspase Dependent Apoptosis of Human Colon Adenocarcinoma HT29 Cell Line through the Modulation of ERK-1/-2, AKT and NF-κB Signaling.Mar Drugs. 2017 Jul 20;15(7):221. doi: 10.3390/md15070221. Mar Drugs. 2017. PMID: 28726723 Free PMC article.
-
Development of Potential Antitumor Agents from the Scaffolds of Plant-Derived Terpenoid Lactones.J Med Chem. 2020 Dec 24;63(24):15410-15448. doi: 10.1021/acs.jmedchem.0c01449. Epub 2020 Dec 8. J Med Chem. 2020. PMID: 33289552 Free PMC article.
-
Asperolide A induces apoptosis and cell cycle arrest of human hepatoma cells with p53-Y220C mutant through p38 mediating phosphorylation of p53 (S33).Heliyon. 2023 Feb 26;9(3):e13843. doi: 10.1016/j.heliyon.2023.e13843. eCollection 2023 Mar. Heliyon. 2023. PMID: 36923828 Free PMC article.
-
Saikosaponin D Inhibits Proliferation and Promotes Apoptosis Through Activation of MKK4-JNK Signaling Pathway in Pancreatic Cancer Cells.Onco Targets Ther. 2020 Sep 24;13:9465-9479. doi: 10.2147/OTT.S263322. eCollection 2020. Onco Targets Ther. 2020. PMID: 33061432 Free PMC article.
References
-
- Jemal A., Bray F., Center M.M., Ferlay J., Ward E., Forman D. Global cancer statistics. CA Cancer. J. Clin. 2011;6:69–90. - PubMed
-
- American Cancer Society Surveillance Research. Cancer Facts and Figures 2004. American Cancer Society; Atlanta, GA, USA: 2004. pp. 1–60.
-
- Shen L., Li Z., Shen S., Niu X., Yu Y., Li Z., Liao M., Chen Z., Lu S. The synergistic effect of EGFR tyrosine kinase inhibitor gefitinib in combination with aromatase inhibitor anastrozole in non-small cell lung cancer cell lines. Lung Cancer. 2012;78:193–200. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous
