Cucurbitacin B inhibits growth and induces apoptosis through the JAK2/STAT3 and MAPK pathways in SH‑SY5Y human neuroblastoma cells

Zheng,Qian; Liu,Yunyi; Liu,Weiwei; Ma,Fengyun; Zhou,Yi; Chen,Mingjie; Chang,Junli; Wang,Yuesheng; Yang,Guangxiao; He,Guangyuan

doi:10.3892/mmr.2014.2175

Cucurbitacin B inhibits growth and induces apoptosis through the JAK2/STAT3 and MAPK pathways in SH‑SY5Y human neuroblastoma cells

Authors:
- Qian Zheng
- Yunyi Liu
- Weiwei Liu
- Fengyun Ma
- Yi Zhou
- Mingjie Chen
- Junli Chang
- Yuesheng Wang
- Guangxiao Yang
- Guangyuan He
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Affiliations: The Genetic Engineering International Cooperation Base of Chinese Ministry of Science and Technology, Key Laboratory of Molecular Biophysics of Chinese Ministry of Education, College of Life Science and Technology, Huazhong University of Science & Technology (HUST), Wuhan, Hubei 430074, P.R. China
Published online on: April 24, 2014 https://doi.org/10.3892/mmr.2014.2175
Pages: 89-94

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Abstract

Cucurbitacin B (CuB) is a tetracyclic triterpene that is contained in extracts from cucurbitaceous plants and has been demonstrated to have anticancer and anti‑inﬂammatory activities. The purpose of the present study was to determine whether CuB exhibits anticancer effects on SH‑SY5Y human neuroblastoma cells and to analyze the underlying molecular mechanism. The results demonstrated that CuB not only induced cell cycle arrest at the G2/M phase, but also induced apoptosis as characterized by positive Annexin V staining, downregulation of phospho‑Janus kinase 2 (p‑JAK2), phospho‑signal transducer and activator of transcription 3 (p‑STAT3), phospho‑extracellular signal‑regulated kinases and the activation of c‑Jun N‑terminal kinase and p38 mitogen activated protein kinase (MAPK). CuB also altered the expression of gene products that mediated cell proliferation (Cyclin B1 and cyclin‑dependent kinase 1), cell survival (B‑cell lymphoma 2, Bcl2‑associated X protein) and increased the expression of p53 and p21. These results provide the evidence that JAK2/STAT3 and MAPKs have crucial roles in CuB‑induced growth inhibition and apoptosis in SH‑SY5Y human neuroblastoma cells.

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1	Brodeur GM: Neuroblastoma: Biological insights into a clinical enigma. Nat Rev Cancer. 3:203–216. 2003. View Article : Google Scholar : PubMed/NCBI
2	Fisher JP and Tweddle DA: Neonatal neuroblastoma. Semin Fetal Neonatal Med. 17:207–215. 2012. View Article : Google Scholar
3	Zhang Y, Ouyang D, Xu L, Ji Y, Zha Q, Cai J and He X: Cucurbitacin B induces rapid depletion of the G-actin pool through reactive oxygen species-dependent actin aggregation in melanoma cells. Acta Biochim Biophys Sin (Shanghai). 43:556–567. 2011. View Article : Google Scholar
4	Jayaprakasam B, Seeram NP and Nair MG: Anticancer and antiinflammatory activities of cucurbitacins from Cucurbita andreana. Cancer Lett. 189:11–16. 2003. View Article : Google Scholar : PubMed/NCBI
5	Chen JC, Chiu MH, Nie RL, Cordell GA and Qiu SX: Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat Prod Rep. 22:386–399. 2005. View Article : Google Scholar : PubMed/NCBI
6	Dzubak P, Hajduch M, Vydra D, et al: Pharmacological activities of natural triterpenoids and their therapeutic implications. Nat Prod Rep. 23:394–411. 2006. View Article : Google Scholar : PubMed/NCBI
7	Takasaki M, Konoshima T, Murata Y, et al: Anticarcinogenic activity of natural sweeteners, cucurbitane glycosides, from Momordica grosvenori. Cancer Lett. 198:37–42. 2003. View Article : Google Scholar : PubMed/NCBI
8	Liu T, Peng H, Zhang M, Deng Y and Wu Z: Cucurbitacin B, a small molecule inhibitor of the Stat3 signaling pathway, enhances the chemosensitivity of laryngeal squamous cell carcinoma cells to cisplatin. Eur J Pharmacol. 641:15–22. 2010. View Article : Google Scholar : PubMed/NCBI
9	Promkan M, Dakeng S, Chakrabarty S, Bögler O and Patmasiriwat P: The effectiveness of cucurbitacin B in BRCA1 defective breast cancer cells. PLoS One. 8:e557322013. View Article : Google Scholar : PubMed/NCBI
10	Haritunians T, Gueller S, Zhang L, et al: Cucurbitacin B induces differentiation, cell cycle arrest, and actin cytoskeletal alterations in myeloid leukemia cells. Leuk Res. 32:1366–1373. 2008. View Article : Google Scholar : PubMed/NCBI
11	Dakeng S, Duangmano S, Jiratchariyakul W, U-Pratya Y, Bögler O and Patmasiriwat P: Inhibition of Wnt signaling by cucurbitacin B in breast cancer cells: reduction of Wnt-associated proteins and reduced translocation of galectin-3-mediated β-catenin to the nucleus. J Cell Biochem. 113:49–60. 2012.PubMed/NCBI
12	Yin D, Wakimoto N, Xing H, et al: Cucurbitacin B markedly inhibits growth and rapidly affects the cytoskeleton in glioblastoma multiforme. Int J Cancer. 123:1364–1375. 2008. View Article : Google Scholar : PubMed/NCBI
13	Thoennissen NH, Iwanski GB, Doan NB, et al: Cucurbitacin B induces apoptosis by inhibition of the JAK/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic cancer cells. Cancer Res. 69:5876–5884. 2009. View Article : Google Scholar
14	Liu T, Zhang M, Zhang H, Sun C and Deng Y: Inhibitory effects of cucurbitacin B on laryngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol. 265:1225–1232. 2008. View Article : Google Scholar : PubMed/NCBI
15	Oh H, Mun YJ, Im SJ, Lee SY, Song HJ, Lee HS and Woo WH: Cucurbitacins from Trichosanthes kirilowii as the inhibitory components on tyrosinase activity and melanin synthesis of B16/F10 melanoma cells. Planta Med. 68:832–833. 2002. View Article : Google Scholar : PubMed/NCBI
16	Lee DH, Thoennissen NH, Goff C, et al: Synergistic effect of low-dose cucurbitacin B and low-dose methotrexate for treatment of human osteosarcoma. Cancer Lett. 306:161–170. 2011. View Article : Google Scholar : PubMed/NCBI
17	Jin HR, Jin X, Dat NT and Lee JJ: Cucurbitacin B suppresses the transactivation activity of RelA/p65. J Cell Biochem. 112:1643–1650. 2011. View Article : Google Scholar : PubMed/NCBI
18	Gheeya JS, Chen QR, Benjamin CD, et al: Screening a panel of drugs with diverse mechanisms of action yields potential therapeutic agents against neuroblastoma. Cancer Biol Ther. 8:2386–2395. 2009. View Article : Google Scholar : PubMed/NCBI
19	Zhang M, Zhang H, Sun C, Shan X, Yang X, Li-Ling J and Deng YH: Targeted constitutive activation of signal transducer and activator of transcription 3 in human hepatocellular carcinoma cells by cucurbitacin B. Cancer Chemother Pharmacol. 63:635–642. 2009. View Article : Google Scholar
20	Mirzayans R, Andrais B, Scott A and Murray D: New insights into p53 signaling and cancer cell response to DNA damage: implications for cancer therapy. J Biomed Biotechnol. 2012:1703252012. View Article : Google Scholar : PubMed/NCBI
21	Kiu H and Nicholson SE: Biology and significance of the JAK/STAT signalling pathways. Growth Factors. 30:88–106. 2012. View Article : Google Scholar : PubMed/NCBI
22	O’Shea JJ, Gadina M and Schreiber RD: Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell. 109(Suppl): S121–S131. 2002.PubMed/NCBI
23	Yu H and Jove R: The STATs of cancer - new molecular targets come of age. Nat Rev Cancer. 4:97–105. 2004. View Article : Google Scholar : PubMed/NCBI
24	Yu H, Pardoll D and Jove R: STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 9:798–809. 2009. View Article : Google Scholar : PubMed/NCBI
25	Liu YY, Zheng Q, Fang B, et al: Germacrone induces apoptosis in human hepatoma HepG2 cells through inhibition of the JAK2/STAT3 signalling pathway. J Huazhong Univ Sci Technolog Med Sci. 33:339–345. 2013. View Article : Google Scholar : PubMed/NCBI
26	Epling-Burnette PK, Liu JH, Catlett-Falcone R, et al: Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest. 107:351–362. 2001. View Article : Google Scholar : PubMed/NCBI
27	Nam S, Xie J, Perkins A, et al: Novel synthetic derivatives of the natural product berbamine inhibit Jak2/Stat3 signaling and induce apoptosis of human melanoma cells. Mol Oncol. 6:484–493. 2012. View Article : Google Scholar : PubMed/NCBI
28	Bill MA, Nicholas C, Mace TA, et al: Structurally modified curcumin analogs inhibit STAT3 phosphorylation and promote apoptosis of human renal cell carcinoma and melanoma cell lines. PLoS One. 7:e407242012. View Article : Google Scholar : PubMed/NCBI
29	Um HJ, Min KJ, Kim DE and Kwon TK: Withaferin A inhibits JAK/STAT3 signaling and induces apoptosis of human renal carcinoma Caki cells. Biochem Biophys Res Commun. 427:24–29. 2012. View Article : Google Scholar : PubMed/NCBI
30	Park KR, Nam D, Yun HM, et al: β-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Lett. 312:178–188. 2011.
31	Scuteri A, Galimberti A, Maggioni D, et al: Role of MAPKs in platinum-induced neuronal apoptosis. Neurotoxicology. 30:312–319. 2009. View Article : Google Scholar : PubMed/NCBI
32	Boutros T, Chevet E and Metrakos P: Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev. 60:261–310. 2008. View Article : Google Scholar : PubMed/NCBI
33	Ishdorj G, Johnston JB and Gibson SB: Cucurbitacin-I (JSI-124) activates the JNK/c-Jun signaling pathway independent of apoptosis and cell cycle arrest in B leukemic cells. BMC Cancer. 11:2682011. View Article : Google Scholar : PubMed/NCBI
34	Cory S and Adams JM: The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2:647–656. 2002. View Article : Google Scholar : PubMed/NCBI
35	Fuster JJ, Sanz-González SM, Moll UM and Andrés V: Classic and novel roles of p53: prospects for anticancer therapy. Trends Mol Med. 13:192–199. 2007. View Article : Google Scholar : PubMed/NCBI