Astaxanthin inhibits gemcitabine‑resistant human pancreatic cancer progression through EMT inhibition and gemcitabine resensitization

Yan,Tao; Li,Hai‑Ying; Wu,Jian‑Song; Niu,Qiang; Duan,Wei‑Hong; Han,Qing‑Zeng; Ji,Wang‑Ming; Zhang,Tao; Lv,Wei

doi:10.3892/ol.2017.6836

Astaxanthin inhibits gemcitabine‑resistant human pancreatic cancer progression through EMT inhibition and gemcitabine resensitization

Authors:
- Tao Yan
- Hai‑Ying Li
- Jian‑Song Wu
- Qiang Niu
- Wei‑Hong Duan
- Qing‑Zeng Han
- Wang‑Ming Ji
- Tao Zhang
- Wei Lv
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Affiliations: Department of Hepatobiliary Surgery, The General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China, Surgical Department, Qinghe County Central Hospital, Qinghe, Xingtai, Hebei 054800, P.R. China
Published online on: August 28, 2017 https://doi.org/10.3892/ol.2017.6836
Pages: 5400-5408
Copyright: © Yan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pancreatic cancer rapidly acquires resistance to chemotherapy resulting in its being difficult to treat. Gemcitabine is the current clinical chemotherapy strategy; however, owing to gemcitabine resistance, it is only able to prolong the life of patients with pancreatic cancer for a limited number of months. Understanding the underlying molecular mechanisms of gemcitabine resistance and selecting a suitable combination of agents for the treatment of pancreatic cancer is required. Astaxanthin (ASX) is able to resensitize gemcitabine‑resistant human pancreatic cancer cells (GR‑HPCCs) to gemcitabine. ASX was identified to upregulate human equilibrative nucleoside transporter 1 (hENT1) and downregulate ribonucleoside diphosphate reductase (RRM) 1 and 2 to enhance gemcitabine‑induced cell death in GR‑HPCCs treated with gemcitabine, and also downregulates TWIST1 and ZEB1 to inhibit the gemcitabine‑induced epithelial‑mesenchymal transition (EMT) phenotype in GR‑HPCCs and to mediate hENT1, RRM1 and RRM2. Furthermore, ASX acts through the hypoxia‑inducible factor 1α/signal transducer and activator of transcription 3 signaling pathway to mediate TWIST1, ZEB1, hENT1, RRM1 and RRM2, regulating the gemcitabine‑induced EMT phenotype and gemcitabine‑induced cell death. Co‑treatment with ASX and gemcitabine in a tumor xenograft model induced by GR‑HPCCs supported the in vitro results. The results of the present study provide a novel therapeutic strategy for the treatment of gemcitabine‑resistant pancreatic cancer.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Diener MK, Combs SE and Büchler MW: Chemoradiotherapy for locally advanced pancreatic cancer. Lancet Oncol. 14:269–270. 2013. View Article : Google Scholar : PubMed/NCBI
3	Akimoto M, Iizuka M, Kanematsu R, Yoshida M and Takenaga K: Anticancer effect of ginger extract against pancreatic cancer cells mainly through reactive oxygen Species-mediated Autotic cell death. PLoS One. 10:e01266052015. View Article : Google Scholar : PubMed/NCBI
4	Seicean A, Petrusel L and Seicean R: New targeted therapies in pancreatic cancer. World J Gastroenterol. 21:6127–6145. 2015. View Article : Google Scholar : PubMed/NCBI
5	Nordh S, Ansari D and Andersson R: hENT1 expression is predictive of gemcitabine outcome in pancreatic cancer: A systematic review. World J Gastroenterol. 20:8482–8490. 2014. View Article : Google Scholar : PubMed/NCBI
6	Poplin E, Wasan H, Rolfe L, Raponi M, Ikdahl T, Bondarenko I, Davidenko I, Bondar V, Garin A, Boeck S, et al: Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: Including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. J Clin Oncol. 31:4453–4461. 2013. View Article : Google Scholar : PubMed/NCBI
7	Wattanawongdon W, Hahnvajanawong C, Namwat N, Kanchanawat S, Boonmars T, Jearanaikoon P, Leelayuwat C, Techasen A and Seubwai W: Establishment and characterization of gemcitabine-resistant human cholangiocarcinoma cell lines with multidrug resistance and enhanced invasiveness. Int J Oncol. 47:398–410. 2015. View Article : Google Scholar : PubMed/NCBI
8	Jordheim LP and Dumontet C: Do hENT1 and RRM1 predict the clinical benefit of gemcitabine in pancreatic cancer? Biomark Med. 7:663–671. 2013. View Article : Google Scholar : PubMed/NCBI
9	Yoneyama H, Takizawa-Hashimoto A, Takeuchi O, Watanabe Y, Atsuda K, Asanuma F, Yamada Y and Suzuki Y: Acquired resistance to gemcitabine and cross-resistance in human pancreatic cancer clones. Anticancer Drugs. 26:90–100. 2015. View Article : Google Scholar : PubMed/NCBI
10	Nakagawa N, Murakami Y, Uemura K, Sudo T, Hashimoto Y, Kondo N and Sueda T: Combined analysis of intratumoral human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) expression is a powerful predictor of survival in patients with pancreatic carcinoma treated with adjuvant gemcitabine-based chemotherapy after operative resection. Surgery. 153:565–575. 2013. View Article : Google Scholar : PubMed/NCBI
11	Bhutia YD, Hung SW, Krentz M, Patel D, Lovin D, Manoharan R, Thomson JM and Govindarajan R: Differential processing of let-7a precursors influences RRM2 expression and chemosensitivity in pancreatic cancer: Role of LIN-28 and SET oncoprotein. PLoS One. 8:e534362013. View Article : Google Scholar : PubMed/NCBI
12	Fisher SB, Fisher KE, Patel SH, Lim MG, Kooby DA, El-Rayes BF, Staley CA III, Adsay NV, Farris AB III and Maithel SK: Excision repair cross-complementing gene-1, ribonucleotide reductase subunit M1, ribonucleotide reductase subunit M2, and human equilibrative nucleoside transporter-1 expression and prognostic value in biliary tract malignancy. Cancer. 119:454–462. 2013. View Article : Google Scholar : PubMed/NCBI
13	Namba T, Kodama R, Moritomo S, Hoshino T and Mizushima T: Zidovudine, an anti-viral drug, resensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibition of the Akt-GSK3β-Snail pathway. Cell Death Dis. 6:e17952015. View Article : Google Scholar : PubMed/NCBI
14	Yi XP, Han T, Li YX, Long XY and Li WZ: Simultaneous silencing of XIAP and survivin causes partial mesenchymal-epithelial transition of human pancreatic cancer cells via the PTEN/PI3K/Akt pathway. Mol Med Rep. 12:601–608. 2015. View Article : Google Scholar : PubMed/NCBI
15	Cheng ZX, Wang DW, Liu T, Liu WX, Xia WB, Xu J, Zhang YH, Qu YK, Guo LQ, Ding L, et al: Effects of the HIF-1α and NF-κB loop on epithelial-mesenchymal transition and chemoresistance induced by hypoxia in pancreatic cancer cells. Oncol Rep. 31:1891–1898. 2014.PubMed/NCBI
16	Rao AR, Sindhuja HN, Dharmesh SM, Sankar KU, Sarada R and Ravishankar GA: Effective inhibition of skin cancer, tyrosinase, and antioxidative properties by astaxanthin and astaxanthin esters from the green alga Haematococcus pluvialis. J Agric Food Chem. 61:3842–3851. 2013. View Article : Google Scholar : PubMed/NCBI
17	Nakao R, Nelson OL, Park JS, Mathison BD, Thompson PA and Chew BP: Effect of dietary astaxanthin at different stages of mammary tumor initiation in BALB/c mice. Anticancer Res. 30:2171–2175. 2010.PubMed/NCBI
18	Vena F, Li Causi E, Rodriguez-Justo M, Goodstal S, Hagemann T, Hartley JA and Hochhauser D: The MEK1/2 inhibitor pimasertib enhances gemcitabine efficacy in pancreatic cancer models by altering ribonucleotide reductase subunit-1 (RRM1). Clin Cancer Res. 21:5563–5577. 2015. View Article : Google Scholar : PubMed/NCBI
19	Lai IL, Chou CC, Lai PT, Fang CS, Shirley LA, Yan R, Mo X, Bloomston M, Kulp SK, Bekaii-Saab T and Chen CS: Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells. Carcinogenesis. 35:2203–2213. 2014. View Article : Google Scholar : PubMed/NCBI
20	D'Angelo RC, Liu XW, Najy AJ, Jung YS, Won J, Chai KX, Fridman R and Kim HR: TIMP-1 via TWIST1 induces EMT phenotypes in human breast epithelial cells. Mol Cancer Res. 12:1324–1233. 2014. View Article : Google Scholar : PubMed/NCBI
21	Díaz-López A, Díaz-Martín J, Moreno-Bueno G, Cuevas EP, Santos V, Olmeda D, Portillo F, Palacios J and Cano A: Zeb1 and Snail1 engage miR-200f transcriptional and epigenetic regulation during EMT. Int J Cancer. 136:E62–E73. 2015. View Article : Google Scholar : PubMed/NCBI
22	Cho KH, Choi MJ, Jeong KJ, Kim JJ, Hwang MH, Shin SC, Park CG and Lee HY: A ROS/STAT3/HIF-1α signaling cascade mediates EGF-induced TWIST1 expression and prostate cancer cell invasion. Prostate. 74:528–536. 2014. View Article : Google Scholar : PubMed/NCBI
23	Zhang W, Shi X, Peng Y, Wu M, Zhang P, Xie R, Wu Y, Yan Q, Liu S and Wang J: HIF-1α promotes epithelial-mesenchymal transition and metastasis through direct regulation of ZEB1 in colorectal cancer. PLoS One. 10:e01296032015. View Article : Google Scholar : PubMed/NCBI
24	Xiong H, Hong J, Du W, Lin YW, Ren LL, Wang YC, Su WY, Wang JL, Cui Y, Wang ZH and Fang JY: Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition. J Biol Chem. 287:5819–5832. 2012. View Article : Google Scholar : PubMed/NCBI
25	Montero TD, Racordon D, Bravo L, Owen GI, Bronfman ML and Leisewitz AV: PPARα and PPARγ regulate the nucleoside transporter hENT1. Biochem Biophys Res Commun. 419:405–411. 2012. View Article : Google Scholar : PubMed/NCBI
26	Lei W, Feng XH, Deng WB, Ni H, Zhang ZR, Jia B, Yang XL, Wang TS, Liu JL, Su RW, et al: Progesterone and DNA damage encourage uterine cell proliferation and decidualization through up-regulating ribonucleotide reductase 2 expression during early pregnancy in mice. J Biol Chem. 287:15174–15192. 2012. View Article : Google Scholar : PubMed/NCBI
27	Kaira K and Yamamoto N: Prognostic and predictive factors in resected non-small-cell lung cancer. Expert Opin Med Diagn. 4:373–381. 2010. View Article : Google Scholar : PubMed/NCBI
28	Tassone P, Di Martino MT, Ventura M, Pietragalla A, Cucinotto I, Calimeri T, Bulotta A, Neri P, Caraglia M and Tagliaferri P: Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo. Cancer Biol Ther. 8:648–653. 2009. View Article : Google Scholar : PubMed/NCBI
29	El-Khoueiry AB, Ramanathan RK, Yang DY, Zhang W, Shibata S, Wright JJ, Gandara D and Lenz HJ: A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer. Invest New Drugs. 30:1175–1183. 2012. View Article : Google Scholar : PubMed/NCBI
30	Kao YT, Hsu WC, Hu HT, Hsu SH, Lin CS, Chiu CC, Lu CY, Hour TC, Pu YS and Huang AM: Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines. Kaohsiung J Med Sci. 30:323–330. 2014. View Article : Google Scholar : PubMed/NCBI
31	Yan Q, Chen P, Wang S, Liu N, Zhao P and Gu A: Association between HIF-1α C1772T/G1790A polymorphisms and cancer susceptibility: An updated systematic review and meta-analysis based on 40 case-control studies. BMC Cancer. 14:9502014. View Article : Google Scholar : PubMed/NCBI
32	Huang C and Xie K: Crosstalk of Sp1 and Stat3 signaling in pancreatic cancer pathogenesis. Cytokine Growth Factor Rev. 23:25–35. 2012. View Article : Google Scholar : PubMed/NCBI