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Article

Ursodeoxycholic acid effectively kills drug-resistant gastric cancer cells through induction of autophagic death

  • Authors:
    • Sung-Chul Lim
    • Song Iy Han
  • View Affiliations / Copyright

    Affiliations: Department of Pathology, Chosun University College of Medicine, Dong-gu, Gwangju 501-759, Republic of Korea, Division of Natural Medical Sciences, College of Health Science, Chosun University, Dong-gu, Gwangju 501-759, Republic of Korea
  • Pages: 1261-1268
    |
    Published online on: June 24, 2015
       https://doi.org/10.3892/or.2015.4076
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Abstract

Carcinoma cells that have acquired drug resistance often exhibit cross-resistance to various other cytotoxic stimuli. Here, we investigated the effects of ursodeoxycholic acid (UDCA), a gastrointestinal tumor-suppressor, on a cisplatin‑resistant SNU601 gastric cancer subline (SNU601/R). While other anticancer drugs, including L-OHP, etoposide, and death ligand TRAIL, had minimal effects on the viability of these resistant cells, they were sensitive to UDCA. The UDCA‑induced reduction in the viability of the SNU601/R cells was accomplished through autophagy while the primary means of cell death in the parental SNU601 cells (SNU601/WT) was apoptosis. Previously, we demonstrated that the UDCA-triggered apoptosis of gastric cancer cells was regulated by a cell surface death receptor, TRAIL-R2/DR5, which was upregulated and re-distributed on lipid rafts. The UDCA stimulation of TRAIL-R2/DR5 also occurred in the SNU601/R cells despite the lack of apoptosis. In the present study, we found that CD95/Fas, another cell surface death receptor, was also translocated into lipid rafts in response to UDCA although it was not involved in the decrease in cell viability. Specifically, raft relocalization of CD95/Fas was triggered by UDCA in the SNU601/WT cells in which apoptosis occurred, but not in the SNU601/R cells where autophagic death occurred. Notably, UDCA reduced ATG5 levels, an essential component of autophagy, in the SNU601/WT, but not in the SNU601/R cell line. Moreover, in CD95/Fas-silenced SNU601/WT cells, UDCA did not decrease ATG5 levels and induced autophagic cell death rather than apoptosis. These results imply that raft‑distributed CD95/Fas may support UDCA-induced apoptosis via downregulation of ATG5 levels, preventing the autophagic pathway. Taken together, these results suggest that UDCA induces both apoptotic and autophagic cell death depending on the intracellular signaling environment, thereby conferring the advantage to overcome drug resistance through apoptotic defects.
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1 

Brozovic A, Fritz G, Christmann M, Zisowsky J, Jaehde U, Osmak M and Kaina B: Long-term activation of SAPK/JNK, p38 kinase and fas-L expression by cisplatin is attenuated in human carcinoma cells that acquired drug resistance. Int J Cancer. 112:974–985. 2004. View Article : Google Scholar : PubMed/NCBI

2 

Komatsu M, Sumizawa T, Mutoh M, Chen ZS, Terada K, Furukawa T, Yang XL, Gao H, Miura N, Sugiyama T, et al: Copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with cisplatin resistance. Cancer Res. 60:1312–1316. 2000.PubMed/NCBI

3 

Taniguchi K, Wada M, Kohno K, Nakamura T, Kawabe T, Kawakami M, Kagotani K, Okumura K, Akiyama S and Kuwano M: A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation. Cancer Res. 56:4124–4129. 1996.PubMed/NCBI

4 

Zhu HJ, Wang JS, Guo QL, Jiang Y and Liu GQ: Reversal of P-glycoprotein mediated multidrug resistance in K562 cell line by a novel synthetic calmodulin inhibitor, E6. Biol Pharm Bull. 28:1974–1978. 2005. View Article : Google Scholar : PubMed/NCBI

5 

McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, Franklin RA, D'Assoro AB, et al: Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 46:249–279. 2006. View Article : Google Scholar : PubMed/NCBI

6 

Wang J, Zhou JY and Wu GS: ERK-dependent MKP-1-mediated cisplatin resistance in human ovarian cancer cells. Cancer Res. 67:11933–11941. 2007. View Article : Google Scholar : PubMed/NCBI

7 

Choi CH, Kim HS, Kweon OS, Lee TB, You HJ, Rha HS, Jeong JH, Lim DY, Min YD, Kim MS, et al: Reactive oxygen species-specific mechanisms of drug resistance in paraquat-resistant acute myelogenous leukemia sublines. Mol Cells. 10:38–46. 2000. View Article : Google Scholar : PubMed/NCBI

8 

Xu Z, Chen ZP, Malapetsa A, Alaoui-Jamali M, Bergeron J, Monks A, Myers TG, Mohr G, Sausville EA, Scudiero DA, et al: DNA repair protein levels vis-à-vis anticancer drug resistance in the human tumor cell lines of the National Cancer Institute drug screening program. Anticancer Drugs. 13:511–519. 2002. View Article : Google Scholar : PubMed/NCBI

9 

Alberts DS, Martínez ME, Hess LM, Einspahr JG, Green SB, Bhattacharyya AK, Guillen J, Krutzsch M, Batta AK, Salen G, et al: Phoenix and Tucson Gastroenterologist Networks: 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

10 

Khare S, Cerda S, Wali RK, von Lintig FC, Tretiakova M, Joseph L, Stoiber D, Cohen G, Nimmagadda K, Hart J, et al: Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclooxygenase-2 expression in colon cancer. Cancer Res. 63:3517–3523. 2003.PubMed/NCBI

11 

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

12 

Lim SC, Duong HQ, Parajuli KR and Han SI: Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells. Oncol Rep. 28:1429–1434. 2012.PubMed/NCBI

13 

Iwasaki I, Sugiyama H, Kanazawa S and Hemmi H: Establishment of cisplatin-resistant variants of human neuroblastoma cell lines, TGW and GOTO, and their drug cross-resistance profiles. Cancer Chemother Pharmacol. 49:438–444. 2002. View Article : Google Scholar : PubMed/NCBI

14 

Sun CL and Chao CC: Cross-resistance to death ligand-induced apoptosis in cisplatin-selected HeLa cells associated with overexpression of DDB2 and subsequent induction of cFLIP. Mol Pharmacol. 67:1307–1314. 2005. View Article : Google Scholar : PubMed/NCBI

15 

Xu H, Choi SM, An CS, Min YD, Kim KC, Kim KJ and Choi CH: Concentration-dependent collateral sensitivity of cisplatin-resistant gastric cancer cell sublines. Biochem Biophys Res Commun. 328:618–622. 2005. View Article : Google Scholar : PubMed/NCBI

16 

Hengartner MO: The biochemistry of apoptosis. Nature. 407:770–776. 2000. View Article : Google Scholar : PubMed/NCBI

17 

Martinou JC and Green DR: Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol. 2:63–67. 2001. View Article : Google Scholar : PubMed/NCBI

18 

Tsujimoto Y: Cell death regulation by the Bcl-2 protein family in the mitochondria. J Cell Physiol. 195:158–167. 2003. View Article : Google Scholar : PubMed/NCBI

19 

Zeuner A, Pedini F, Signore M, Ruscio G, Messina C, Tafuri A, Girelli G, Peschle C and De Maria R: Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells. Blood. 107:3495–3502. 2006. View Article : Google Scholar

20 

Müllauer L, Gruber P, Sebinger D, Buch J, Wohlfart S and Chott A: Mutations in apoptosis genes: A pathogenetic factor for human disease. Mutat Res. 488:211–231. 2001. View Article : Google Scholar : PubMed/NCBI

21 

Perego P, Giarola M, Righetti SC, Supino R, Caserini C, Delia D, Pierotti MA, Miyashita T, Reed JC and Zunino F: Association between cisplatin resistance and mutation of p53 gene and reduced bax expression in ovarian carcinoma cell systems. Cancer Res. 56:556–562. 1996.PubMed/NCBI

22 

Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gélinas C, Fan Y, et al: Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 10:51–64. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Hippert MM, O'Toole PS and Thorburn A: Autophagy in cancer: Good, bad, or both? Cancer Res. 66:9349–9351. 2006. View Article : Google Scholar : PubMed/NCBI

24 

Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H and Levine B: Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 402:672–676. 1999. View Article : Google Scholar : PubMed/NCBI

25 

Syntichaki P and Tavernarakis N: The biochemistry of neuronal necrosis: Rogue biology? Nat Rev Neurosci. 4:672–684. 2003. View Article : Google Scholar : PubMed/NCBI

26 

Vakkila J and Lotze MT: Inflammation and necrosis promote tumour growth. Nat Rev Immunol. 4:641–648. 2004. View Article : Google Scholar : PubMed/NCBI

27 

Zong WX and Thompson CB: Necrotic death as a cell fate. Genes Dev. 20:1–15. 2006. View Article : Google Scholar : PubMed/NCBI

28 

Bernales S, McDonald KL and Walter P: Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4:e4232006. View Article : Google Scholar : PubMed/NCBI

29 

Eisenberg-Lerner A, Bialik S, Simon HU and Kimchi A: Life and death partners: Apoptosis, autophagy and the cross-talk between them. Cell Death Differ. 16:966–975. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Moretti L, Cha YI, Niermann KJ and Lu B: Switch between apoptosis and autophagy: Radiation-induced endoplasmic reticulum stress? Cell Cycle. 6:793–798. 2007. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Lim S and Han SI: Ursodeoxycholic acid effectively kills drug-resistant gastric cancer cells through induction of autophagic death. Oncol Rep 34: 1261-1268, 2015.
APA
Lim, S., & Han, S.I. (2015). Ursodeoxycholic acid effectively kills drug-resistant gastric cancer cells through induction of autophagic death. Oncology Reports, 34, 1261-1268. https://doi.org/10.3892/or.2015.4076
MLA
Lim, S., Han, S. I."Ursodeoxycholic acid effectively kills drug-resistant gastric cancer cells through induction of autophagic death". Oncology Reports 34.3 (2015): 1261-1268.
Chicago
Lim, S., Han, S. I."Ursodeoxycholic acid effectively kills drug-resistant gastric cancer cells through induction of autophagic death". Oncology Reports 34, no. 3 (2015): 1261-1268. https://doi.org/10.3892/or.2015.4076
Copy and paste a formatted citation
x
Spandidos Publications style
Lim S and Han SI: Ursodeoxycholic acid effectively kills drug-resistant gastric cancer cells through induction of autophagic death. Oncol Rep 34: 1261-1268, 2015.
APA
Lim, S., & Han, S.I. (2015). Ursodeoxycholic acid effectively kills drug-resistant gastric cancer cells through induction of autophagic death. Oncology Reports, 34, 1261-1268. https://doi.org/10.3892/or.2015.4076
MLA
Lim, S., Han, S. I."Ursodeoxycholic acid effectively kills drug-resistant gastric cancer cells through induction of autophagic death". Oncology Reports 34.3 (2015): 1261-1268.
Chicago
Lim, S., Han, S. I."Ursodeoxycholic acid effectively kills drug-resistant gastric cancer cells through induction of autophagic death". Oncology Reports 34, no. 3 (2015): 1261-1268. https://doi.org/10.3892/or.2015.4076
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