Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells

Lim,Sung-Chul; Duong,Hong-Quan; Parajuli,Keshab  Raj; Han,Song  Iy

doi:10.3892/or.2012.1918

Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells

Authors:
- Sung-Chul Lim
- Hong-Quan Duong
- Keshab Raj Parajuli
- Song Iy Han
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Affiliations: Research Center for Resistant Cells, Chosun University, Gwangju 501-759, Republic of Korea
Published online on: July 19, 2012 https://doi.org/10.3892/or.2012.1918
Pages: 1429-1434

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Abstract

Ursodeoxycholic acid (UDCA) has been regarded as a suppressor of gastrointestinal cancer, but the mechanisms underlying its antitumor effects are not fully understood. Previously, we reported the antitumor effect of UDCA by demonstrating that UDCA induces apoptosis of gastric cancer cells. Bile acids are known to activate the ERK pathway and ERK is a representative oncogenic kinase in cancer cells. Here, we investigated the role of ERK in UDCA-induced gastric cancer cell apoptosis. We found that UDCA enhanced the phosphorylation of ERK1/2 and MEK1/2. The prevention of MEK by the pharmacologic inhibitors PD98059 and U0126, resulted in decreased UDCA-induced apoptosis as shown by the reduction of apoptotic body formation, caspase-8 activity, and caspase-3, -6 and PARP cleavage, indicating that ERK exerts pro-apoptotic activity upon exposure to UDCA. In addition, U0126 reduced UDCA-triggered TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) expression. In gene silencing studies, we observed that RNA interference of ERK2 decreased apoptosis and reduced DR5 overexpression. Lipid raft disrupting agent, methyl-β-cyclodextrin, blunted the phosphorylation of ERK1/2, indicating that ERK activation is regulated in a lipid raft-dependent manner. On the other hand, tumor-promoting bile acid, deoxycholic acid (DCA), also phosphorylated ERK in SNU601 cells. However, the DCA-triggered ERK pathway exerted anti-apoptotic function in the cells. Suppression of the ERK pathway enhanced DCA-induced apoptosis, and ERK activation was observed to be lipid raft-independently controlled. These results indicated that UDCA and DCA may cause differential responses in gastric cancer cells through the ERK signaling molecule. Thus, ERK activation may be a possible mechanism by which UDCA and DCA represent differential activities in gastrointestinal cancer.

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1	Greim H, Trulzsch D, Czygan P, Rudick J, Hutterer F, Schaffner F and Popper H: Mechanism of cholestasis. 6. Bile acids in human livers with or without biliary obstruction. Gastroenterology. 63:846–850. 1972.PubMed/NCBI
2	Qiao L, Studer E, Leach K, McKinstry R, Gupta S, Decker R, Kukreja R, Valerie K, Nagarkatti P, El Deiry W, et al: Deoxycholic acid (DCA) causes ligand-independent activation of epidermal growth factor receptor (EGFR) and FAS receptor in primary hepatocytes: inhibition of EGFR/mitogen-activated protein kinase-signaling module enhances DCA-induced apoptosis. Mol Biol Cell. 12:2629–2645. 2001. View Article : Google Scholar
3	Loddenkemper C, Keller S, Hanski ML, Cao M, Jahreis G, Stein H, Zeitz M and Hanski C: Prevention of colitis-associated carcinogenesis in a mouse model by diet supplementation with ursodeoxycholic acid. Int J Cancer. 118:2750–2757. 2006. View Article : Google Scholar
4	Alberts DS, Martinez ME, Hess LM, Einspahr JG, Green SB, Bhattacharyya AK, Guillen J, Krutzsch M, Batta AK, Salen G, et al: Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence. J Natl Cancer Inst. 97:846–853. 2005. View Article : Google Scholar : PubMed/NCBI
5	Qiao D, Stratagouleas ED and Martinez JD: Activation and role of mitogen-activated protein kinases in deoxycholic acid-induced apoptosis. Carcinogenesis. 22:35–41. 2001. View Article : Google Scholar : PubMed/NCBI
6	Rust C, Karnitz LM, Paya CV, Moscat J, Simari RD and Gores GJ: The bile acid taurochenodeoxycholate activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. J Biol Chem. 275:20210–20216. 2000. View Article : Google Scholar : PubMed/NCBI
7	Higuchi H and Gores GJ: Bile acid regulation of hepatic physiology: IV. Bile acids and death receptors. Am J Physiol Gastrointest Liver Physiol. 284:G734–G738. 2003. View Article : Google Scholar : PubMed/NCBI
8	Higuchi H, Grambihler A, Canbay A, Bronk SF and Gores GJ: Bile acids up-regulate death receptor 5/TRAIL-receptor 2 expression via a c-Jun N-terminal kinase-dependent pathway involving Sp1. J Biol Chem. 279:51–60. 2004. View Article : Google Scholar : PubMed/NCBI
9	Higuchi H, Bronk SF, Taniai M, Canbay A and Gores GJ: Cholestasis increases tumor necrosis factor-related apoptotis-inducing ligand (TRAIL)-R2/DR5 expression and sensitizes the liver to TRAIL-mediated cytotoxicity. J Pharmacol Exp Ther. 303:461–467. 2002. View Article : Google Scholar
10	Higuchi H, Bronk SF, Takikawa Y, Werneburg N, Takimoto R, El-Deiry W and Gores GJ: The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis. J Biol Chem. 276:38610–38618. 2001. View Article : Google Scholar : PubMed/NCBI
11	Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 270:1326–1331. 1995. View Article : Google Scholar : PubMed/NCBI
12	Qiao L, Han SI, Fang Y, Park JS, Gupta S, Gilfor D, Amorino G, Valerie K, Sealy L, Engelhardt JF, et al: Bile acid regulation of C/EBPbeta, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes. Mol Cell Biol. 23:3052–3066. 2003. View Article : Google Scholar : PubMed/NCBI
13	Looby E, Abdel-Latif MM, Athie-Morales V, Duggan S, Long A and Kelleher D: Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells. BMC Cancer. 9:1902009. View Article : Google Scholar : PubMed/NCBI
14	Baek MK, Park JS, Park JH, Kim MH, Kim HD, Bae WK, Chung IJ, Shin BA and Jung YD: Lithocholic acid upregulates uPAR and cell invasiveness via MAPK and AP-1 signaling in colon cancer cells. Cancer Lett. 290:123–128. 2010. View Article : Google Scholar : PubMed/NCBI
15	Liao M, Zhao J, Wang T, Duan J, Zhang Y and Deng X: Role of bile salt in regulating Mcl-1 phosphorylation and chemoresistance in hepatocellular carcinoma cells. Mol Cancer. 10:442011. View Article : Google Scholar : PubMed/NCBI
16	Oka H, Chatani Y, Hoshino R, Ogawa O, Kakehi Y, Terachi T, Okada Y, Kawaichi M, Kohno M and Yoshida O: Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. Cancer Res. 55:4182–4187. 1995.PubMed/NCBI
17	Sivaraman VS, Wang H, Nuovo GJ and Malbon CC: Hyperexpression of mitogen-activated protein kinase in human breast cancer. J Clin Invest. 99:1478–1483. 1997. View Article : Google Scholar : PubMed/NCBI
18	Lim SC, Duong HQ, Choi JE, Lee TB, Kang JH, Oh SH and Han SI: Lipid raft-dependent death receptor 5 (DR5) expression and activation are critical for ursodeoxycholic acid-induced apoptosis in gastric cancer cells. Carcinogenesis. 32:723–731. 2011. View Article : Google Scholar : PubMed/NCBI
19	Lim SC, Choi JE, Kang HS and Si H: Ursodeoxycholic acid switches oxaliplatin-induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53-caspase 8 pathway in HepG2 hepatocellular carcinoma. Int J Cancer. 126:1582–1595. 2010.
20	Zhao Y, Zhao X, Yang B, Neuzil J and Wu K: alpha-Tocopheryl succinate-induced apoptosis in human gastric cancer cells is modulated by ERK1/2 and c-Jun N-terminal kinase in a biphasic manner. Cancer Lett. 247:345–352. 2007. View Article : Google Scholar
21	Schweyer S, Soruri A, Meschter O, Heintze A, Zschunke F, Miosge N, Thelen P, Schlott T, Radzun HJ and Fayyazi A: Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation. Br J Cancer. 91:589–598. 2004. View Article : Google Scholar : PubMed/NCBI
22	Singh S, Upadhyay AK, Ajay AK and Bhat MK: p53 regulates ERK activation in carboplatin induced apoptosis in cervical carcinoma: a novel target of p53 in apoptosis. FEBS Lett. 581:289–295. 2007. View Article : Google Scholar : PubMed/NCBI
23	Wang X, Martindale JL and Holbrook NJ: Requirement for ERK activation in cisplatin-induced apoptosis. J Biol Chem. 275:39435–39443. 2000. View Article : Google Scholar
24	Woessmann W, Chen X and Borkhardt A: Ras-mediated activation of ERK by cisplatin induces cell death independently of p53 in osteosarcoma and neuroblastoma cell lines. Cancer Chemother Pharmacol. 50:397–404. 2002. View Article : Google Scholar : PubMed/NCBI
25	Amran D, Sancho P, Fernandez C, Esteban D, Ramos AM, de Blas E, Gomez M, Palacios MA and Aller P: Pharmacological inhibitors of extracellular signal-regulated protein kinases attenuate the apoptotic action of cisplatin in human myeloid leukemia cells via glutathione-independent reduction in intracellular drug accumulation. Biochim Biophys Acta. 1743:269–279. 2005. View Article : Google Scholar
26	Im E and Martinez JD: Ursodeoxycholic acid (UDCA) can inhibit deoxycholic acid (DCA)-induced apoptosis via modulation of EGFR/Raf-1/ERK signaling in human colon cancer cells. J Nutr. 134:483–486. 2004.PubMed/NCBI
27	Lee HY, Crawley S, Hokari R, Kwon S and Kim YS: Bile acid regulates MUC2 transcription in colon cancer cells via positive EGFR/PKC/Ras/ERK/CREB, PI3K/Akt/IkappaB/NF-kappaB and p38/MSK1/CREB pathways and negative JNK/c-Jun/AP-1 pathway. Int J Oncol. 36:941–953. 2010.PubMed/NCBI