Browse > Article
http://dx.doi.org/10.5352/JLS.2012.22.6.760

Induction of Apoptosis and Antitumor Activity by Stichoposide D through the Generation of Ceramide in Human Leukemia Cells  

Park, Eun-Seon (Department of Boichemistry, Dong-A University College of Medicine)
Yun, Seung-Hoon (Department of Boichemistry, Dong-A University College of Medicine)
Shin, Sung-Won (Department of Boichemistry, Dong-A University College of Medicine)
Kwak, Jong-Young (Department of Boichemistry, Dong-A University College of Medicine)
Park, Joo-In (Department of Boichemistry, Dong-A University College of Medicine)
Publication Information
Journal of Life Science / v.22, no.6, 2012 , pp. 760-771 More about this Journal
Abstract
Marine triterpene glycosides are physiologically active natural compounds isolated from sea cucumbers(holothurians). It was demonstrated that they have a wide range of biological activities, including antifungal, cytotoxic, and antitumor effects. A previous study showed that stichoposide C (STC) isolated from Thelenota anax induces apoptosis through generation of ceramide by activation of acid sphingomyelinase (SMase) and neutral SMase in human leukemia cells. In this study, we investigated whether STD, a structural analog of STC, can induce apoptosis and examined the molecular mechanisms for its activity. It was found that STC and STD induce apoptosis in a dose- and time-dependent manner and lead to the activation of caspase-8, mitochondrial damage, activation of caspase-9, and activation of caspase-3 in K562 and HL-60 cells. STC activates acid SMase and neutral SMase, which results in the generation of ceramide. Specific inhibition of acid SMase or neutral SMase partially blocked STC-induced apoptosis, but not STD-induced apoptosis. In contrast, STD generates ceramide through the activation of ceramide synthase. Specific inhibition of ceramide synthase partially blocked STD-induced apoptosis, but not STC-induced apoptosis. Moreover, STC and STD markedly reduced tumor growth of HL-60 xenograft tumors and increased ceramide generation in vivo. These results indicate that STC and STD can induce apoptosis and have antitumor activity through the different molecular mechanisms, because they have a different sugar residue attached to aglycones. Thus, these results suggest that their actions are affected by a sugar residue attached to aglycones and they can be used as anticancer agents in the treatment of leukemia.
Keywords
Stichoposide D; ceramide; ceramide synthase; apoptosis; antitumor activity;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Brown, D. A. and London, E. 1998. Functions of lipid rafts in biological membranes. Annu. Rev. Cell. Dev. Biol. 14, 111-136.   DOI
2 Charruyer, A., Grazide, S., Bezombes, C., Muller, S., Laurent, G. and Jaffre' zou, J. P. 2005. UV-C light induces raft-associated acid sphingomyelinase and JNK activation and translocation independently on a nuclear signal. J. Biol. Chem. 280, 19196-19204.   DOI
3 Dbaibo, G .S., El-Assaad, W., Krikorian, A., Liu, B., Diab, K., Idriss, N. Z., El-Sabban, M., Driscoll, T. A., Perry, D. K. and Hannun, Y. A. 2001. Ceramide generation by two distinct pathways in tumor necrosis factor $\alpha$-induced cell death. FEBS Lett. 503, 7-12.   DOI
4 Della Peruta, M., Martinelli, G., Moratti, E., Pintani, D., Vezzalini, M., Mafficini, A., Grafone, T., Iacobucci, I., Soverini, S., Murineddu, M., Vinante, F., Tecchio, C., Piras, G., Gabbas, A., Monne, M. and Sorio, C. 2010. Protein tyrosine phosphatase receptor type $\gamma$ is a functional tumor suppressor gene specifically downregulated in chronic myeloid leukemia. Cancer Res. 70, 8896-8906.   DOI
5 Fulda, S. and Debatin, K. M. 2006. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25, 4798-4811.   DOI
6 Goni, F. M. and Alonso, A. 2002. Sphingomyelinases: enzymology and membrane activity. FEBS Lett. 531, 38-46.   DOI
7 Green, D. R. and Reed, J. C. 1976. Mitochondria and apoptosis. Science 281, 1309-1312.
8 Green, D. R. and Kroemer, G. 1998. The central executioners of apoptosis: caspases or mitochondria? Trends Cell Biol. 8, 267-271.   DOI
9 Gulbins, E. and Kolesnick, R. 2002. Acid sphingomyelinase- derived ceramide signaling in apoptosis. Subcell. Biochem. 36, 229-244.
10 Han, H., Shin, S. W., Seo, C. Y., Kwon, H. C., Han, J. Y., Kim, I. H., Kwak, J. Y. and Park, J. I. 2007. 15-Deoxy$\Delta^{12,14}$-prostaglandin $J_{2}$ (15d-$PGJ_{2}$) sensitizes human leukemic HL-60 cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through Akt downregulation. Apoptosis 12, 2101-2114.   DOI
11 Hannun, Y. A. and Obeid, L. M. 2008. Principles of bioactive lipid signaling: lessons from sphingolipids. Nat. Rev. Mol. Cell. Biol. 9, 139-150.   DOI
12 Kolesnick, R. N., Goni, F. M. and Alonso, A. 2000. Compartmentalization of ceramide signaling: physical foundations and biological effects. J. Cell Physiol. 184, 285-300.   DOI
13 Pettit, G. R., Herald, C. L. and Herald, D. L. 1976. Antineoplastic agents XLV: sea cucumber cytotoxic saponins. J. Pharm. Sci. 65, 1558-1559.   DOI
14 Levade, T. and Jaffrezou, J. P. 1999. Signalling sphingomyelinases: which, where, how and why? Biochim. Biophys. Acta 1438, 1-17.   DOI
15 Ogretmen, B. and Hannun, Y. A. 2004. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer 4, 604-616.   DOI
16 Perrotti, D., Jamieson, C., Goldman, J. and Skorski, T. 2010. Chronic myeloid leukemia: mechanisms of blastic transformation. J. Clin. Invest. 120, 2254-2264.   DOI
17 Saglio, G., Kim, D. W., Issaragrisil, S., le Coutre, P., Etienne, G., Lobo, C., Pasquini, R., Clark, R. E., Hochhaus, A., Hughes, T. P., Gallagher, N., Hoenekopp, A., Dong, M., Haque, A., Larson, R. A., Kantarjian, H. M.; ENESTnd Investigators. 2010. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 362, 2251-2259.   DOI
18 Schiffer, C. A. 2007. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N. Engl. J. Med. 357, 258-265.   DOI   ScienceOn
19 Shin, S. W., Seo, C. Y., Han, H., Han, J. Y., Jeong, J. S., Kwak, J. Y. and Park, J. I. 2009. 15d-$PGJ_{2}$ induces apoptosis by reactive oxygen species-mediated inactivation of Akt in leukemia and colorectal cancer cells and shows in vivo antitumor activity. Clin. Cancer Res. 15, 5414-5425.   DOI
20 Stonik, V. A., Maltsev, I. I., Kalinovsky, A. I., Conde, K. and Elyakov, G. B. 1982. Glycosides of marine-invertebrates. XI. The two novel triterpene glycosides from holothorian of Stichopodidae family. Chem. Nat. Prod. 194-199.
21 Stonik, V. A. 1986. Some terpenoid and steroid derivatives from echinoderms and sponges. Pure Appl. Chem. 58, 423-436.   DOI
22 Yun, S. H. 2010. Clarification of molecular mechanism for stichoposide C (STC)-induced apoptosis of human leukemia cells. MS. Thesis, Dong-A University, Busan, Korea.
23 Stonik, V. A., Kalinin, V. I. and Avilov, S. A. 1999. Toxins from sea cucumbers (holothuroids): Chemical structures, properties, taxonomic distribution, biosynthesis and evolution. J. Nat. Toxins 8, 235-248.
24 Strum, J. C., Ghosh, S. and Bell, R. M. 1997. Lipid second messengers. A role in cell growth regulation and cell cycle regulation. Adv. Exp. Mol. Biol. 407, 421-431.   DOI
25 Taha, T. A., Mullen, T. D. and Obeid, L. M. 2006. A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death. Biochim. Biophys. Acta 1758, 2027-2036.   DOI