Corosolic acid reduces 5‑FU chemoresistance in human gastric cancer cells by activating AMPK

Park,Jun  Beom; Lee,Jin  Sun; Lee,Myung  Sun; Cha,Eun  Young; Kim,Soyeon; Sul,Ji  Young

doi:10.3892/mmr.2018.9244

Corosolic acid reduces 5‑FU chemoresistance in human gastric cancer cells by activating AMPK

Authors:
- Jun Beom Park
- Jin Sun Lee
- Myung Sun Lee
- Eun Young Cha
- Soyeon Kim
- Ji Young Sul
View Affiliations

Affiliations: Department of Surgery, Chungnam National University Hospital, Daejeon 35015, Republic of Korea, Biomedical Research Institute, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
Published online on: July 3, 2018 https://doi.org/10.3892/mmr.2018.9244
Pages: 2880-2888
Copyright: © Park et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

5‑Fluorouracil (5‑FU) is one of the most commonly used chemotherapeutic agents for gastric cancer. Resistance to 5‑FU‑based chemotherapy remains the major obstacle in the treatment of gastric cancer. A growing body of evidence has suggested that adenosine monophosphate‑activated protein kinase (AMPK) is pivotal for chemoresistance. However, the mechanism by which AMPK regulates the chemosensitivity of gastric cancer remains unclear. In the present study, how corosolic acid enhanced the chemosensitivity of gastric cancer cells to 5‑FU via AMPK activation was investigated. A 5‑FU‑resistant gastric cancer cell line (SNU‑620/5‑FUR) was established, which had a marked increase in thymidine synthase (TS) expression but reduced AMPK phosphorylation when compared with the parental cell line, SNU‑620. AMPK regulation by 5‑aminoimidazole‑4‑carboxamide ribonucleotide or compound c was revealed to be markedly associated with TS expression and 5‑FU‑resistant cell viability. In addition, corosolic acid activated AMPK, and decreased TS expression and the phosphorylation of mammalian target of rapamycin/4E‑binding protein 1 in a dose‑dependent manner. Corosolic acid treatment significantly reduced cell viability while compound c reversed corosolic acid‑induced cell growth inhibition. The 5‑FU‑resistance sensitization effect of corosolic acid was determined by the synergistic reduction of TS expression and inhibition of cell viability in the presence of 5‑FU. The corosolic acid‑induced AMPK activation was markedly increased by additional 5‑FU treatment, while compound c reversed AMPK phosphorylation. In addition, compound c treatment reversed corosolic acid‑induced apoptotic markers such as capase‑3 and PARP cleavage, and cytochrome c translocation to cytosol, in the presence of 5‑FU. Corosolic acid treatment in the presence of 5‑FU induced an increase in the apoptotic cell population based on flow cytometry analysis. This increase was abolished by compound c. In conclusion, these results implied that corosolic acid may have therapeutic potential to sensitize the resistance of gastric cancer to 5‑FU by activating AMPK.

View Figures

View References

1	Smith JK, McPhee JT, Hill JS, Whalen GF, Sullivan ME, Litwin DE, Anderson FA and Tseng JF: National outcomes after gastric resection for neoplasm. Arch Surg. 142:387–393. 2007. View Article : Google Scholar : PubMed/NCBI
2	Tsai MM, Wang CS, Tsai CY, Chi HC, Tseng YH and Lin KH: Potential prognostic, diagnostic and therapeutic markers for human gastric cancer. World J Gastroenterol. 20:13791–13803. 2014. View Article : Google Scholar : PubMed/NCBI
3	Zhang N, Yin Y, Xu SJ and Chen WS: 5-Fluorouracil: Mechanisms of resistance and reversal strategies. Molecules. 13:1551–1569. 2008. View Article : Google Scholar : PubMed/NCBI
4	Scartozzi M, Maccaroni E, Giampieri R, Pistelli M, Bittoni A, Del Prete M, Berardi R and Cascinu S: 5-Fluorouracil pharmacogenomics: Still rocking after all these years? Pharmacogenomics. 12:251–265. 2011. View Article : Google Scholar : PubMed/NCBI
5	Johnston PG, Lenz HJ, Leichman CG, Danenberg KD, Allegra CJ, Danenberg PV and Leichman L: Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 55:1407–1412. 1995.PubMed/NCBI
6	Saga Y, Suzuki M, Mizukami H, Urabe M, Fukushima M, Ozawa K and Sato I: Enhanced expression of thymidylate synthase mediates resistance of uterine cervical cancer cells to radiation. Oncology. 63:185–191. 2002. View Article : Google Scholar : PubMed/NCBI
7	Copur S, Aiba K, Drake JC, Allegra CJ and Chu E: Thymidylate synthase gene amplification in human colon cancer cell lines resistant to 5-fluorouracil. Biochem Pharmacol. 49:1419–1426. 1995. View Article : Google Scholar : PubMed/NCBI
8	Fakhrejahani E, Miyamoto A and Tanigawa N: Correlation between thymidylate synthase and dihydropyrimidine dehydrogenase mRNA level and in vitro chemosensitivity to 5-fluorouracil, in relation to differentiation in gastric cancer. Cancer Chemother Pharmacol. 60:437–446. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kim YH, Liang H, Liu X, Lee JS, Cho JY, Cheong JH, Kim H, Li M, Downey TJ, Dyer MD, et al: AMPKα modulation in cancer progression: Multilayer integrative analysis of the whole transcriptome in Asian gastric cancer. Cancer Res. 72:2512–2521. 2012. View Article : Google Scholar : PubMed/NCBI
10	Ling S, Tian Y, Zhang H, Jia K, Feng T, Sun D, Gao Z, Xu F, Hou Z, Li Y and Wang L: Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel-7402/5-fluorouracil cells. Mol Med Rep. 10:2891–2897. 2014. View Article : Google Scholar : PubMed/NCBI
11	Qu C, Zhang W, Zheng G, Zhang Z, Yin J and He Z: Metformin reverses multidrug resistance and epithelial-mesenchymal transition (EMT) via activating AMP-activated protein kinase (AMPK) in human breast cancer cells. Mol Cell Biochem. 386:63–71. 2014. View Article : Google Scholar : PubMed/NCBI
12	Wu Y, Qi Y, Liu H, Wang X, Zhu H and Wang Z: AMPK activator AICAR promotes 5-FU-induced apoptosis in gastric cancer cells. Mol Cell Biochem. 411:299–305. 2016. View Article : Google Scholar : PubMed/NCBI
13	Hua HW, Jiang F, Huang Q, Liao ZJ and Ding G: Re-sensitization of 5-FU resistance by SPARC through negative regulation of glucose metabolism in hepatocellular carcinoma. Tumour Biol. 36:303–313. 2015. View Article : Google Scholar : PubMed/NCBI
14	Hou W, Li Y, Zhang Q, Wei X, Peng A, Chen L and Wei Y: Triterpene acids isolated from Lagerstroemia speciosa leaves as alpha-glucosidase inhibitors. Phytother Res. 23:614–618. 2009. View Article : Google Scholar : PubMed/NCBI
15	Thuong PT, Min BS, Jin W, Na M, Lee J, Seong R, Lee YM, Song K, Seong Y, Lee HK, et al: Anti-complementary activity of ursane-type triterpenoids from Weigela subsessilis. Biol Pharm Bull. 29:830–833. 2006. View Article : Google Scholar : PubMed/NCBI
16	Fukushima M, Matsuyama F, Ueda N, Egawa K, Takemoto J, Kajimoto Y, Yonaha N, Miura T, Kaneko T, Nishi Y, et al: Effect of corosolic acid on postchallenge plasma glucose levels. Diabetes Res Clin Pract. 73:174–177. 2006. View Article : Google Scholar : PubMed/NCBI
17	Miura T, Ueda N, Yamada K, Fukushima M, Ishida T, Kaneko T, Matsuyama F and Seino Y: Antidiabetic effects of corosolic acid in KK-Ay diabetic mice. Biol Pharm Bull. 29:585–587. 2006. View Article : Google Scholar : PubMed/NCBI
18	Xu Y, Zhao Y, Xu Y, Guan Y, Zhang X, Chen Y, Wu Q, Zhu G, Chen Y, Sun F, et al: Blocking inhibition to YAP by ActinomycinD enhances anti-tumor efficacy of Corosolic acid in treating liver cancer. Cell Signal. 29:209–217. 2017. View Article : Google Scholar : PubMed/NCBI
19	Sung B, Kang YJ, Kim DH, Hwang SY, Lee Y, Kim M, Yoon JH, Kim CM, Chung HY and Kim ND: Corosolic acid induces apoptotic cell death in HCT116 human colon cancer cells through a caspase-dependent pathway. Int J Mol Med. 33:943–949. 2014. View Article : Google Scholar : PubMed/NCBI
20	Nho KJ, Chun JM and Kim HK: Corosolic acid induces apoptotic cell death in human lung adenocarcinoma A549 cells in vitro. Food Chem Toxicol. 56:8–17. 2013. View Article : Google Scholar : PubMed/NCBI
21	Lee HS, Park JB, Lee MS, Cha EY, Kim JY and Sul JY: Corosolic acid enhances 5-fluorouracil-induced apoptosis against SNU-620 human gastric carcinoma cells by inhibition of mammalian target of rapamycin. Mol Med Rep. 12:4782–4788. 2015. View Article : Google Scholar : PubMed/NCBI
22	Lee MS, Cha EY, Thuong PT, Kim JY, Ahn MS and Sul JY: Down-regulation of human epidermal growth factor receptor 2/neu oncogene by corosolic acid induces cell cycle arrest and apoptosis in NCI-N87 human gastric cancer cells. Biol Pharm Bull. 33:931–937. 2010. View Article : Google Scholar : PubMed/NCBI
23	Yang J, Leng J, Li JJ, Tang JF, Li Y, Liu BL and Wen XD: Corosolic acid inhibits adipose tissue inflammation and ameliorates insulin resistance via AMPK activation in high-fat fed mice. Phytomedicine. 23:181–190. 2016. View Article : Google Scholar : PubMed/NCBI
24	Li Y, Zhou ZH, Chen MH, Yang J, Leng J, Cao GS, Xin GZ, Liu LF, Kou JP, Liu BL, et al: Inhibition of mitochondrial fission and NOX2 expression prevent NLRP3 inflammasome activation in the endothelium: The role of corosolic acid action in the amelioration of endothelial dysfunction. Antioxid Redox Signal. 24:893–908. 2016. View Article : Google Scholar : PubMed/NCBI
25	Lee MS, Lee CM, Cha EY, Thuong PT, Bae K, Song IS, Noh SM and Sul JY: Activation of AMP-activated protein kinase on human gastric cancer cells by apoptosis induced by corosolic acid isolated from Weigela subsessilis. Phytother Res. 24:1857–1861. 2010. View Article : Google Scholar : PubMed/NCBI
26	Goel A and Aggarwal BB: Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. Nutr Cancer. 62:919–930. 2010. View Article : Google Scholar : PubMed/NCBI
27	Tang H, Zhang X, Cui S, Wang J, Ruan Q, Huang Y and Yang D: Role and mechanism research on reversal of 5-fluorouracil resistance by epigallocatechin gallate in gastric cancer drug-resistance cells lines SGC-7901/5-FU. Zhonghua Wei Chang Wai Ke Za Zhi. 19:1170–1175. 2016.(In Chinese). PubMed/NCBI
28	Liao F, Yang Z, Lu X, Guo X and Dong W: Sinomenine sensitizes gastric cancer cells to 5-fluorouracil in vitro and in vivo. Oncol Lett. 6:1604–1610. 2013. View Article : Google Scholar : PubMed/NCBI
29	Kato K, Gong J, Iwama H, Kitanaka A, Tani J, Miyoshi H, Nomura K, Mimura S, Kobayashi M, Aritomo Y, et al: The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo. Mol Cancer Ther. 11:549–560. 2012. View Article : Google Scholar : PubMed/NCBI
30	Kim DC, Park KR, Jeong YJ, Yoon H, Ahn MJ, Rho GJ, Lee J, Gong YD and Han SY: Resistance to the c-Met inhibitor KRC-108 induces the epithelial transition of gastric cancer cells. Oncol Lett. 11:991–997. 2016. View Article : Google Scholar : PubMed/NCBI
31	Holohan C, Van Schaeybroeck S, Longley DB and Johnston PG: Cancer drug resistance: An evolving paradigm. Nat Rev Cancer. 13:714–726. 2013. View Article : Google Scholar : PubMed/NCBI
32	Wang W and Guan KL: AMP-activated protein kinase and cancer. Acta Physiol (Oxf). 196:55–63. 2009. View Article : Google Scholar : PubMed/NCBI
33	Hadad SM, Baker L, Quinlan PR, Robertson KE, Bray SE, Thomson G, Kellock D, Jordan LB, Purdie CA, Hardie DG, et al: Histological evaluation of AMPK signaling in primary breast cancer. BMC Cancer. 9:3072009. View Article : Google Scholar : PubMed/NCBI
34	Liu X, Chhipa RR, Nakano I and Dasgupta B: The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent. Mol Cancer Ther. 13:596–605. 2014. View Article : Google Scholar : PubMed/NCBI
35	Tseng CH: Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus. Aging (Albany NY). 8:1636–1649. 2016. View Article : Google Scholar : PubMed/NCBI
36	Gao H, Xie J, Peng J, Han Y, Jiang Q, Han M and Wang C: Hispidulin inhibits proliferation and enhances chemosensitivity of gallbladder cancer cells by targeting HIF-1α. Exp Cell Res. 332:236–246. 2015. View Article : Google Scholar : PubMed/NCBI