Osthole enhances TRAIL-mediated apoptosis through downregulation of c-FLIP expression in renal carcinoma Caki cells

Min,Kyoung-Jin; Han,Min Ae; Kim,Shin; Park,Jong-Wook; Kwon,Taeg Kyu

doi:10.3892/or.2017.5490

Osthole enhances TRAIL-mediated apoptosis through downregulation of c-FLIP expression in renal carcinoma Caki cells

Authors:
- Kyoung-Jin Min
- Min Ae Han
- Shin Kim
- Jong-Wook Park
- Taeg Kyu Kwon
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Affiliations: Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704-701, Republic of Korea
Published online on: March 6, 2017 https://doi.org/10.3892/or.2017.5490
Pages: 2348-2354

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Abstract

Osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, has been shown to induce various beneficial biochemical effects such as anti-inflammatory and antitumor. In the present study, we examined whether osthole could sensitize TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma Caki cells. We found that osthole and TRAIL alone, had no effect on apoptosis, but combined treatment with osthole and TRAIL markedly induced apoptosis in Caki (renal carcinoma), U251MG (glioma) and MDA-MB-231 (breast carcinoma) cells. In contrast, combined treatment with osthole and TRAIL did not induce apoptosis in normal human skin fibroblast cells. Osthole induced downregulation of cellular FLICE-like inhibitory protein (c-FLIP) expression, and overexpression of c-FLIP markedly blocked apoptosis induced by the combined treatment with osthole and TRAIL. In addition, osthole markedly reduced mitochondrial membrane potential levels, and increased cytosolic cytochrome c release in combined treatment with osthole and TRAIL. Therefore, these data suggest that osthole may be an efficient TRAIL sensitizer.

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1	Maas M, Deters AM and Hensel A: Anti-inflammatory activity of Eupatorium perfoliatum L. extracts, eupafolin, and dimeric guaianolide via iNOS inhibitory activity and modulation of inflammation-related cytokines and chemokines. J Ethnopharmacol. 137:371–381. 2011. View Article : Google Scholar : PubMed/NCBI
2	Chung KS, Choi JH, Back NI, Choi MS, Kang EK, Chung HG, Jeong TS and Lee KT: Eupafolin, a flavonoid isolated from Artemisia princeps, induced apoptosis in human cervical adenocarcinoma HeLa cells. Mol Nutr Food Res. 54:1318–1328. 2010. View Article : Google Scholar : PubMed/NCBI
3	Liu K, Park C, Chen H, Hwang J, Thimmegowda NR, Bae EY, Lee KW, Kim HG, Liu H, Soung NK, et al: Eupafolin suppresses prostate cancer by targeting phosphatidylinositol 3-kinase-mediated Akt signaling. Mol Carcinog. 54:751–760. 2015. View Article : Google Scholar : PubMed/NCBI
4	Kim SR, Park MJ, Lee MK, Sung SH, Park EJ, Kim J, Kim SY, Oh TH, Markelonis GJ and Kim YC: Flavonoids of Inula britannica protect cultured cortical cells from necrotic cell death induced by glutamate. Free Radic Biol Med. 32:596–604. 2002. View Article : Google Scholar : PubMed/NCBI
5	Wen YC, Lee WJ, Tan P, Yang SF, Hsiao M, Lee LM and Chien MH: By inhibiting snail signaling and miR-23a-3p, osthole suppresses the EMT-mediated metastatic ability in prostate cancer. Oncotarget. 6:21120–21136. 2015. View Article : Google Scholar : PubMed/NCBI
6	Xu XM, Zhang Y, Qu D, Feng XW, Chen Y and Zhao L: Osthole suppresses migration and invasion of A549 human lung cancer cells through inhibition of matrix metalloproteinase-2 and matrix metallopeptidase-9 in vitro. Mol Med Rep. 6:1018–1022. 2012.PubMed/NCBI
7	Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA, et al: Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 3:673–682. 1995. View Article : Google Scholar : PubMed/NCBI
8	Wang S and El-Deiry WS: TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 22:8628–8633. 2003. View Article : Google Scholar : PubMed/NCBI
9	Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ and Ashkenazi A: Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity. 12:611–620. 2000. View Article : Google Scholar : PubMed/NCBI
10	Walczak H, Bouchon A, Stahl H and Krammer PH: Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2- or Bcl-x_L-overexpressing chemotherapy-resistant tumor cells. Cancer Res. 60:3051–3057. 2000.PubMed/NCBI
11	Kelly MM, Hoel BD and Voelkel-Johnson C: Doxorubicin pretreatment sensitizes prostate cancer cell lines to TRAIL induced apoptosis which correlates with the loss of c-FLIP expression. Cancer Biol Ther. 1:520–527. 2002. View Article : Google Scholar : PubMed/NCBI
12	Ng CP, Zisman A and Bonavida B: Synergy is achieved by complementation with Apo2L/TRAIL and actinomycin D in Apo2L/TRAIL-mediated apoptosis of prostate cancer cells: Role of XIAP in resistance. Prostate. 53:286–299. 2002. View Article : Google Scholar : PubMed/NCBI
13	Jin Z, McDonald ER III, Dicker DT and El-Deiry WS: Deficient tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor transport to the cell surface in human colon cancer cells selected for resistance to TRAIL-induced apoptosis. J Biol Chem. 279:35829–35839. 2004. View Article : Google Scholar : PubMed/NCBI
14	Zhang Y and Zhang B: TRAIL resistance of breast cancer cells is associated with constitutive endocytosis of death receptors 4 and 5. Mol Cancer Res. 6:1861–1871. 2008. View Article : Google Scholar : PubMed/NCBI
15	Jo HS, Yeo HJ, Cha HJ, Kim SJ, Cho SB, Park JH, Lee CH, Yeo EJ, Choi YJ, Eum WS, et al: Transduced Tat-DJ-1 protein inhibits cytokines-induced pancreatic RINm5F cell death. BMB Rep. 49:297–302. 2016. View Article : Google Scholar : PubMed/NCBI
16	Han EH, Kim HG, Lee EJ and Jeong HG: Endosulfan induces CYP1A1 expression mediated through aryl hydrocarbon receptor signal transduction by protein kinase C. Toxicol Res. 31:339–345. 2015. View Article : Google Scholar : PubMed/NCBI
17	Kim S, Lee TJ, Leem J, Choi KS, Park JW and Kwon TK: Sanguinarine-induced apoptosis: Generation of ROS, down-regulation of Bcl-2, c-FLIP, and synergy with TRAIL. J Cell Biochem. 104:895–907. 2008. View Article : Google Scholar : PubMed/NCBI
18	Zhang L, Jiang G, Yao F, He Y, Liang G, Zhang Y, Hu B, Wu Y, Li Y and Liu H: Growth inhibition and apoptosis induced by osthole, a natural coumarin, in hepatocellular carcinoma. PLoS One. 7:e378652012. View Article : Google Scholar : PubMed/NCBI
19	Wang L, Yang L, Lu Y, Chen Y, Liu T, Peng Y, Zhou Y, Cao Y, Bi Z, Liu T, et al: Osthole induces cell cycle arrest and inhibits migration and invasion via PTEN/Akt pathways in osteosarcoma. Cell Physiol Biochem. 38:2173–2182. 2016. View Article : Google Scholar : PubMed/NCBI
20	Ding Y, Lu X, Hu X, Ma J and Ding H: Osthole inhibits proliferation and induces apoptosis in human osteosarcoma cells. Int J Clin Pharmacol Ther. 52:112–117. 2014. View Article : Google Scholar : PubMed/NCBI
21	Oyarzo MP, Medeiros LJ, Atwell C, Feretzaki M, Leventaki V, Drakos E, Amin HM and Rassidakis GZ: c-FLIP confers resistance to FAS-mediated apoptosis in anaplastic large-cell lymphoma. Blood. 107:2544–2547. 2006. View Article : Google Scholar : PubMed/NCBI
22	Zhou XD, Yu JP, Liu J, Luo HS, Chen HX and Yu HG: Overexpression of cellular FLICE-inhibitory protein (FLIP) in gastric adenocarcinoma. Clin Sci. 106:397–405. 2004. View Article : Google Scholar : PubMed/NCBI
23	Ryu BK, Lee MG, Chi SG, Kim YW and Park JH: Increased expression of cFLIP_L in colonic adenocarcinoma. J Pathol. 194:15–19. 2001. View Article : Google Scholar : PubMed/NCBI
24	Li X, Pan X, Zhang H, Lei D, Liu D, Xu F and Luan X: Overexpression of cFLIP in head and neck squamous cell carcinoma and its clinicopathologic correlations. J Cancer Res Clin Oncol. 134:609–615. 2008. View Article : Google Scholar : PubMed/NCBI
25	Jung KJ, Min KJ, Bae JH and Kwon TK: Carnosic acid sensitized TRAIL-mediated apoptosis through down-regulation of c-FLIP and Bcl-2 expression at the post translational levels and CHOP-dependent up-regulation of DR5, Bim, and PUMA expression in human carcinoma caki cells. Oncotarget. 6:1556–1568. 2015. View Article : Google Scholar : PubMed/NCBI
26	Lv S, Zhang Y, Yan M, Mao H, Pan C, Gan M, Fan J and Wang G: Inhibition of osteolysis after local administration of osthole in a TCP particles-induced osteolysis model. Int Orthop. 40:1545–1552. 2016. View Article : Google Scholar : PubMed/NCBI