ERK/GSK3β signaling is involved in atractylenolide I-induced apoptosis and cell cycle arrest in melanoma cells

Ye,Yan; Chao,Xiao-Juan; Wu,Jin-Feng; Cheng,Brian  Chi-Yan; Su,Tao; Fu,Xiu-Qiong; Li,Ting; Guo,Hui; Tse,Anfernee  Kai-Wing; Kwan,Hiu-Yee; Du,Juan; Chou,Gui-Xin; Yu,Zhi-Ling

doi:10.3892/or.2015.4111

ERK/GSK3β signaling is involved in atractylenolide I-induced apoptosis and cell cycle arrest in melanoma cells

Authors:
- Yan Ye
- Xiao-Juan Chao
- Jin-Feng Wu
- Brian Chi-Yan Cheng
- Tao Su
- Xiu-Qiong Fu
- Ting Li
- Hui Guo
- Anfernee Kai-Wing Tse
- Hiu-Yee Kwan
- Juan Du
- Gui-Xin Chou
- Zhi-Ling Yu
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Affiliations: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
Published online on: July 6, 2015 https://doi.org/10.3892/or.2015.4111
Pages: 1543-1548

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Abstract

Novel agents need to be developed to overcome the limitations of the current melanoma therapeutics. Atractylenolide I (AT-I) is a sesquiterpene compound isolated from atractylodis macrocephalae rhizoma. Previous findings demonstrated that AT-I exhibited cytotoxic action in melanoma cells. However, the molecular mechanisms of AT‑1's anti-melanoma properties remain to be elucidated. In the present study, the cell cycle-arrest and apoptosis-promoting effects as well as the ERK/GSK3β signaling-related mechanism of action of AT-I were examined. B16 melanoma cells were treated with various concentrations of AT-1 (50, 75 and 100 µM) for 48 or 72 h. Cell cycle and apoptosis were analyzed by flow cytometry. Protein expression levels were detected by western blot analysis. AT-I treatment induced G1 phase arrest, which was accompanied by increased p21 and decreased CDK2 protein expression levels. Apoptosis was observed after AT-I treatment for 72 h, which was accompanied by activated caspase‑3 and ‑8. AT-I treatment significantly decreased phospho-ERK, phospho-GSK3β, c-Jun and increased p53 protein expression levels. Lithium chloride (LiCl, 5 mM), a GSK3β inhibitor, treatment alone did not increase the apoptosis of B16 cells, while pretreatment with LiCl markedly reversed AT-I-induced apoptosis. Additionally, AT-I-induced G1 phase arrest was partially reversed by LiCl pretreatment. In conclusion, ERK/GSK3β signaling was involved in the apoptotic and G1 phase arrest effects of AT-I in melanoma cells.

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1	Sladden MJ, Balch C, Barzilai DA, Berg D, Freiman A, Handiside T, Hollis S, Lens MB and Thompson JF: Surgical excision margins for primary cutaneous melanoma. Cochrane Database Syst Rev. pp. CD0048352009, View Article : Google Scholar
2	Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 363:711–723. 2010. View Article : Google Scholar : PubMed/NCBI
3	Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 364:2517–2526. 2011. View Article : Google Scholar : PubMed/NCBI
4	Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, et al: Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 363:809–819. 2010. View Article : Google Scholar : PubMed/NCBI
5	Kudchadkar RR, Gonzalez R and Lewis K: New targeted therapies in melanoma. Cancer Control. 20:282–288. 2013.PubMed/NCBI
6	Bauer BA: Herbal therapy: What a clinician needs to know to counsel patients effectively. Mayo Clin Proc. 75:835–841. 2000. View Article : Google Scholar : PubMed/NCBI
7	Endo K, Taguchi T, Taguchi F, Hikino H, Yamahara J and Fujimura H: Antiinflammatory principles of Atractylodes rhizomes. Chem Pharm Bull (Tokyo). 27:2954–2958. 1979. View Article : Google Scholar
8	Kiso Y, Tohkin M and Hikino H: Mechanism of antihepatotoxic activity of atractylon, I: Effect on free radical generation and lipid peroxidation. Planta Med. 51:97–100. 1985. View Article : Google Scholar
9	Mori H, Xu Q, Sakamoto O, Uesugi Y, Koda A and Nishioka I: Mechanisms of antitumor activity of aqueous extracts from Chinese herbs: Their immunopharmacological properties. Jpn J Pharmacol. 49:423–431. 1989. View Article : Google Scholar : PubMed/NCBI
10	Kang TH, Bang JY, Kim MH, Kang IC, Kim HM and Jeong HJ: Atractylenolide III, a sesquiterpenoid, induces apoptosis in human lung carcinoma A549 cells via mitochondria-mediated death pathway. Food Chem Toxicol. 49:514–519. 2011. View Article : Google Scholar
11	Yan Ye, Chou GX, Hui Wang, Chu JH, Fong WF and Yu ZL: Effects of sesquiterpenes isolated from largehead atractylodes rhizome on growth, migration, and differentiation of B16 melanoma cells. Integr Cancer Ther. 10:92–100. 2011. View Article : Google Scholar
12	el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B: WAF1, a potential mediator of p53 tumor suppression. Cell. 75:817–825. 1993. View Article : Google Scholar : PubMed/NCBI
13	Ehrhardt H, Häcker S, Wittmann S, Maurer M, Borkhardt A, Toloczko A, Debatin KM, Fulda S and Jeremias I: Cytotoxic drug-induced, p53-mediated upregulation of caspase-8 in tumor cells. Oncogene. 27:783–793. 2008. View Article : Google Scholar
14	Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GV and Jope RS: Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage. Proc Natl Acad Sci USA. 99:7951–7955. 2002. View Article : Google Scholar : PubMed/NCBI
15	Eom TY, Roth KA and Jope RS: Neural precursor cells are protected from apoptosis induced by trophic factor withdrawal or genotoxic stress by inhibitors of glycogen synthase kinase 3. J Biol Chem. 282:22856–22864. 2007. View Article : Google Scholar : PubMed/NCBI
16	Schreiber M, Kolbus A, Piu F, Szabowski A, Möhle-Steinlein U, Tian J, Karin M, Angel P and Wagner EF: Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev. 13:607–619. 1999. View Article : Google Scholar : PubMed/NCBI
17	Lopez-Bergami P, Huang C, Goydos JS, Yip D, Bar-Eli M, Herlyn M, Smalley KS, Mahale A, Eroshkin A, Aaronson S, et al: Rewired ERK-JNK signaling pathways in melanoma. Cancer Cell. 11:447–460. 2007. View Article : Google Scholar : PubMed/NCBI
18	Sherr CJ and Roberts JM: CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes Dev. 13:1501–1512. 1999. View Article : Google Scholar : PubMed/NCBI
19	Shao J, Teng Y, Padia R, Hong S, Noh H, Xie X, Mumm JS, Dong Z, Ding HF, Cowell J, et al: COP1 and GSK3β cooperate to promote c-Jun degradation and inhibit breast cancer cell tumorigenesis. Neoplasia. 15:1075–1085. 2013. View Article : Google Scholar : PubMed/NCBI
20	Dihlmann S, Klein S and Doeberitz Mv Mv: Reduction of beta-catenin/T-cell transcription factor signaling by aspirin and indomethacin is caused by an increased stabilization of phosphorylated beta-catenin. Mol Cancer Ther. 2:509–516. 2003.PubMed/NCBI
21	Gao Y, Liu Z, Zhang X, He J, Pan Y, Hao F, Xie L, Li Q, Qiu X and Wang E: Inhibition of cytoplasmic GSK-3β increases cisplatin resistance through activation of Wnt/β-catenin signaling in A549/DDP cells. Cancer Lett. 336:231–239. 2013. View Article : Google Scholar : PubMed/NCBI
22	Novetsky AP, Thompson DM, Zighelboim I, Thaker PH, Powell MA, Mutch DG and Goodfellow PJ: Lithium chloride and inhibition of glycogen synthase kinase 3β as a potential therapy for serous ovarian cancer. Int Gynecol Cancer. 23:361–366. 2013. View Article : Google Scholar
23	Grimaldi AM, Cassidy PB, Leachmann S and Ascierto PA: Novel approaches in melanoma prevention and therapy. Cancer Treat Res. 159:443–455. 2014. View Article : Google Scholar
24	el-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, et al: WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 54:1169–1174. 1994.PubMed/NCBI
25	Toyoshima H and Hunter T: p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 78:67–74. 1994. View Article : Google Scholar : PubMed/NCBI
26	Peter M and Herskowitz I: Joining the complex: Cyclin-dependent kinase inhibitory proteins and the cell cycle. Cell. 79:181–184. 1994. View Article : Google Scholar : PubMed/NCBI
27	Ashkenazi A and Dixit VM: Death receptors: Signaling and modulation. Science. 281:1305–1308. 1998. View Article : Google Scholar : PubMed/NCBI
28	Doble BW and Woodgett JR: GSK-3: Tricks of the trade for a multi-tasking kinase. J Cell Sci. 116:1175–1186. 2003. View Article : Google Scholar : PubMed/NCBI
29	Jope RS and Johnson GV: The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 29:95–102. 2004. View Article : Google Scholar : PubMed/NCBI
30	Jope RS, Yuskaitis CJ and Beurel E: Glycogen synthase kinase-3 (GSK3): Inflammation, diseases, and therapeutics. Neurochem Res. 32:577–595. 2007. View Article : Google Scholar :
31	Liu Y, Ye F, Qiu GQ, Zhang M, Wang R, He QY and Cai Y: Effects of lactone I from Atractylodes macrocephala Koidz on cytokines and proteolysis-inducing factors in cachectic cancer patients. Di Yi Jun Yi Da Xue Xue Bao. 25:1308–1311. 2005.In Chinese. PubMed/NCBI
32	Liu Y, Jia Z, Dong L, Wang R and Qiu G: A randomized pilot study of atractylenolide I on gastric cancer cachexia patients. Evid Based Complement Altemat Med. 5:337–344. 2008. View Article : Google Scholar
33	Wang C, Wang S, Chen Q and He L: A capillary gas chromatography-selected ion monitoring mass spectrometry method for the analysis of atractylenolide I in rat plasma and tissues, and application in a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 863:215–222. 2008. View Article : Google Scholar : PubMed/NCBI