Anticancer effect of arsenite on cell migration, cell cycle and apoptosis in human pancreatic cancer cells

Horibe,Yohei; Adachi,Seiji; Yasuda,Ichiro; Yamauchi,Takahiro; Kawaguchi,Junji; Kozawa,Osamu; Shimizu,Masahito; Moriwaki,Hisataka

doi:10.3892/ol.2016.4564

Anticancer effect of arsenite on cell migration, cell cycle and apoptosis in human pancreatic cancer cells

Authors:
- Yohei Horibe
- Seiji Adachi
- Ichiro Yasuda
- Takahiro Yamauchi
- Junji Kawaguchi
- Osamu Kozawa
- Masahito Shimizu
- Hisataka Moriwaki
View Affiliations

Affiliations: Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan, Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan
Published online on: May 13, 2016 https://doi.org/10.3892/ol.2016.4564
Pages: 177-182

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

The standard treatment for advanced pancreatic cancer is chemotherapy, but its clinical outcome remains unsatisfactory. Therefore, the development of novel treatments for this malignancy is urgently required. In the present study, the anticancer effect of arsenite on platelet-derived growth factor (PDGF)‑BB‑induced migration, cell cycle and apoptosis was investigated in pancreatic cancer cells (AsPC‑1 and BxPC‑3), and compared with the effect on normal pancreatic epithelial (PE) cells. In the cell migration assay, arsenite clearly inhibited PDGF‑BB‑induced cell migration in AsPC‑1 cells, but not in BxPC‑3 or PE cells. Arsenite also caused cell apoptosis in AsPC‑1 cells, but not in BxPC‑3 or PE cells. In AsPC‑1 cells, the levels of cyclin D1 and phosphorylated retinoblastoma protein decreased following treatment with arsenite, but this was not observed in BxPC‑3 cells. To further examine the differences between these two cell lines, the effect of arsenite on upstream p44/p42 mitogen‑activated protein kinase (MAPK) and Akt was investigated. PDGF‑BB caused phosphorylation of p44/p42 MAPK and Akt in both cell lines. Pretreatment with arsenite significantly suppressed PDGF‑BB‑induced phosphorylation of Akt, but not of p44/p42 MAPK in AsPC‑1 cells. By contrast, arsenite did not affect these molecules in BxPC‑3 cells. Since the inhibition of the Akt signaling pathway markedly reduced PDGF‑BB‑induced migration in AsPC‑1 cells, the present results strongly suggest that arsenite inhibits PDGF‑BB‑induced migration by suppressing the Akt signaling pathway in AsPC‑1 cells. Therefore, arsenite may be a useful tool for the treatment of patients with certain types of pancreatic cancer, without causing adverse effects on normal pancreatic cells.

View Figures

View References

1	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar : PubMed/NCBI
2	Chao Y, Wu CY, Wang JP, Lee RC, Lee WP and Li CP: A randomized controlled trial of gemcitabine plus cisplatin versus gemcitabine alone in the treatment of metastatic pancreatic cancer. Cancer Chemother. Pharmacol. 72:637–642. 2013.
3	Vincent A, Herman J, Schulick R, Hruban RH and Goggins M: Pancreatic cancer. Lancet. 378:607–620. 2011. View Article : Google Scholar : PubMed/NCBI
4	Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, et al: National Cancer Institute of Canada Clinical Trials Group: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 25:1960–1966. 2007. View Article : Google Scholar : PubMed/NCBI
5	Stathis A and Moore MJ: Advanced pancreatic carcinoma: Current treatment and future challenges. Nat Rev Clin Oncol. 7:163–172. 2010. View Article : Google Scholar : PubMed/NCBI
6	Borad MJ, Reddy SG, Bahary N, Uronis HE, Sigal D, Cohn AL, Schelman WR, Stephenson J Jr, Chiorean EG, Rosen PJ, et al: Randomized phase II trial of gemcitabine plus TH-302 versus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 33:1475–1481. 2015. View Article : Google Scholar : PubMed/NCBI
7	Chen CT, Chen YC, Yamaguchi H and Hung MC: Carglumic acid promotes apoptosis and suppresses cancer cell proliferation in vitro and in vivo. Am J Cancer Res. 5:3560–3569. 2015.PubMed/NCBI
8	Waxman S and Anderson KC: History of the development of arsenic derivatives in cancer therapy. Oncologist. 6(Suppl 2): 3–10. 2001. View Article : Google Scholar : PubMed/NCBI
9	Dangleben NL, Skibola CF and Smith MT: Arsenic immunotoxicity: A review. Environ. Health. 12:732013.
10	Hynes RO and Lander AD: Contact and adhesive specificities in the associations, migrations, and targeting of cells and axons. Cell. 68:303–322. 1992. View Article : Google Scholar : PubMed/NCBI
11	Burridge K: Are stress fibres contractile? Nature. 294:691–692. 1981. View Article : Google Scholar : PubMed/NCBI
12	Humphries JD, Wang P, Streuli C, Geiger B, Humphries MJ and Ballestrem C: Vinculin controls focal adhesion formation by direct interactions with talin and actin. J Cell Biol. 179:1043–1057. 2007. View Article : Google Scholar : PubMed/NCBI
13	Burridge K and Chrzanowska-Wodnicka M: Focal adhesions, contractility, and signaling. Annu Rev Cell Dev Biol. 12:463–518. 1996. View Article : Google Scholar : PubMed/NCBI
14	Henriksen R, Funa K, Wilander E, Bäckström T, Ridderheim M and Oberg K: Expression and prognostic significance of platelet-derived growth factor and its receptors in epithelial ovarian neoplasms. Cancer Res. 53:4550–4554. 1993.PubMed/NCBI
15	Uren A, Merchant MS, Sun CJ, Vitolo MI, Sun Y, Tsokos M, Illei PB, Ladanyi M, Passaniti A, Mackall C and Toretsky JA: Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells. Oncogene. 22:2334–2342. 2003. View Article : Google Scholar : PubMed/NCBI
16	Yamauchi T, Adachi S, Yasuda I, Nakashima M, Kawaguchi J, Nishii Y, Yoshioka T, Okano Y, Hirose Y, Kozawa O and Moriwaki H: UVC radiation induces downregulation of EGF receptor via phosphorylation at serine 1,046/1,047 in human pancreatic cancer cells. Radiat Res. 176:565–574. 2011. View Article : Google Scholar : PubMed/NCBI
17	Adachi S, Nagao T, Ingolfsson HI, Maxfield FR, Andersen OS, Kopelovich L and Weinstein IB: The inhibitory effect of (−)-epigallocatechin gallate on activation of the epidermal growth factor receptor is associated with altered lipid order in HT29 colon cancer cells. Cancer Res. 67:6493–6501. 2007. View Article : Google Scholar : PubMed/NCBI
18	Glienke W, Chow KU, Bauer N and Bergmann L: Down-regulation of wt1 expression in leukemia cell lines as part of apoptotic effect in arsenic treatment using two compounds. Leuk Lymphoma. 47:1629–1638. 2006. View Article : Google Scholar : PubMed/NCBI
19	Nicolis I, Curis E, Deschamps P and Bénazeth S: Arsenite medicinal use, metabolism, pharmacokinetics and monitoring in human hair. Biochimie. 91:1260–1267. 2009. View Article : Google Scholar : PubMed/NCBI
20	Gao M, Dong W, Hu M, Yu M, Guo L, Qian L, Guo N and Song L: GADD45alpha mediates arsenite-induced cell apoptotic effect in human hepatoma cells via JNKs/AP-1-dependent pathway. J Cell Biochem. 109:1264–1273. 2010.PubMed/NCBI
21	Oliver FJ, de la Rubia G, Rolli V, Ruiz-Ruiz MC, de Murcia G and Murcia JM: Importance of poly(ADP-ribose) polymerase and its cleavage in apoptosis. Lesson from an uncleavable mutant. J Biol Chem. 273:33533–33539. 1998. View Article : Google Scholar : PubMed/NCBI
22	Sherr CJ: Cancer cell cycles. Science. 274:1672–1677. 1996. View Article : Google Scholar : PubMed/NCBI
23	Henson ES and Gibson SB: Surviving cell death through epidermal growth factor (EGF) signal transduction pathways: Implications for cancer therapy. Cell Signal. 18:2089–2097. 2006. View Article : Google Scholar : PubMed/NCBI
24	Cheng JQ, Lindsley CW, Cheng GZ, Yang H and Nicosia SV: The Akt/PKB pathway: Molecular target for cancer drug discovery. Oncogene. 24:7482–7492. 2005. View Article : Google Scholar : PubMed/NCBI
25	Cross DA, Alessi DR, Cohen P, Andjelkovich M and Hemmings BA: Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 378:785–789. 1995. View Article : Google Scholar : PubMed/NCBI
26	Sutherland C, Leighton IA and Cohen P: Inactivation of glycogen synthase kinase-3 beta by phosphorylation: New kinase connections in insulin and growth-factor signalling. Biochem J. 296:15–19. 1993. View Article : Google Scholar : PubMed/NCBI
27	Nakashima M, Adachi S, Yasuda I, Yamauchi T, Kozawa O and Moriwaki H: Rho-kinase regulates negatively the epidermal growth factor-stimulated colon cancer cell proliferation. Int J Oncol. 36:585–592. 2010.PubMed/NCBI