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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Saikosaponin d induces cell death through caspase-3-dependent, caspase-3-independent and mitochondrial pathways in mammalian hepatic stellate cells

Authors: Ming-Feng Chen, S. Joseph Huang, Chao-Cheng Huang, Pei-Shan Liu, Kun-I Lin, Ching-Wen Liu, Wen-Chuan Hsieh, Li-Yen Shiu, Chang-Han Chen

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Saikosaponin d (SSd) is one of the main active triterpene saponins in Bupleurum falcatum. It has a steroid-like structure, and is reported to have pharmacological activities, including liver protection in rat, cell cycle arrest and apoptosis induction in several cancer cell lines. However, the biological functions and molecular mechanisms of mammalian cells under SSd treatment are still unclear.

Methods

The cytotoxicity and apoptosis of hepatic stellate cells (HSCs) upon SSd treatment were discovered by MTT assay, colony formation assay and flow cytometry. The collage I/III, caspase activity and apoptotic related genes were examined by quantitative PCR, Western blotting, immunofluorescence and ELISA. The mitochondrial functions were monitored by flow cytometry, MitoTracker staining, ATP production and XF24 bioenergetic assay.

Results

This study found that SSd triggers cell death via an apoptosis path. An example of this path might be typical apoptotic morphology, increased sub-G1 phase cell population, inhibition of cell proliferation and activation of caspase-3 and caspase-9. However, the apoptotic effects induced by SSd are partially blocked by the caspase-3 inhibitor, Z-DEVD-FMK, suggesting that SSd may trigger both HSC-T6 and LX-2 cell apoptosis through caspase-3-dependent and independent pathways. We also found that SSd can trigger BAX and BAK translocation from the cytosol to the mitochondria, resulting in mitochondrial function inhibition, membrane potential disruption. Finally, SSd also increases the release of apoptotic factors.

Conclusions

The overall analytical data indicate that SSd-elicited cell death may occur through caspase-3-dependent, caspase-3-independent and mitochondrial pathways in mammalian HSCs, and thus can delay the formation of liver fibrosis by reducing the level of HSCs.
Literature
1.
Furre IE, Moller MT, Shahzidi S, Nesland JM, Peng Q. Involvement of both caspase-dependent and -independent pathways in apoptotic induction by hexaminolevulinate-mediated photodynamic therapy in human lymphoma cells. Apoptosis. 2006;11(11):2031–42.CrossRefPubMed
2.
Liu X, Zhu ST, You H, Cong M, Liu TH, Wang BE, Jia JD. Hepatitis B virus infects hepatic stellate cells and affects their proliferation and expression of collagen type I. Chin Med J (Engl). 2009;122(12):1455–61.
3.
Chiang LC, Ng LT, Liu LT, Shieh DE, Lin CC. Cytotoxicity and anti-hepatitis B virus activities of saikosaponins from Bupleurum species. Planta Med. 2003;69(8):705–9.CrossRefPubMed
4.
Bermejo Benito P, Abad Martinez MJ, Silvan Sen AM, Sanz Gomez A, Fernandez Matellano L, Sanchez Contreras S, Diaz Lanza AM. In vivo and in vitro antiinflammatory activity of saikosaponins. Life Sci. 1998;63(13):1147–56.CrossRefPubMed
5.
Dang SS, Wang BF, Cheng YA, Song P, Liu ZG, Li ZF. Inhibitory effects of saikosaponin-d on CCl4-induced hepatic fibrogenesis in rats. World J Gastroenterol. 2007;13(4):557–63.CrossRefPubMedPubMedCentral
6.
Kato M, Pu MY, Isobe K, Iwamoto T, Nagase F, Lwin T, Zhang YH, Hattori T, Yanagita N, Nakashima I. Characterization of the immunoregulatory action of saikosaponin-d. Cell Immunol. 1994;159(1):15–25.CrossRefPubMed
7.
Ushio Y, Abe H. Inactivation of measles virus and herpes simplex virus by saikosaponin d. Planta Med. 1992;58(2):171–3.CrossRefPubMed
8.
Wu SJ, Lin YH, Chu CC, Tsai YH, Chao JC. Curcumin or saikosaponin a improves hepatic antioxidant capacity and protects against CCl4-induced liver injury in rats. J Med Food. 2008;11(2):224–9.CrossRefPubMed
9.
Fan J, Li X, Li P, Li N, Wang T, Shen H, Siow Y, Choy P, Gong Y. Saikosaponin-d attenuates the development of liver fibrosis by preventing hepatocyte injury. Biochem Cell Biol. 2007;85(2):189–95.CrossRefPubMed
10.
Tundis R, Bonesi M, Deguin B, Loizzo MR, Menichini F, Conforti F, Tillequin F, Menichini F. Cytotoxic activity and inhibitory effect on nitric oxide production of triterpene saponins from the roots of Physospermum verticillatum (Waldst & Kit) (Apiaceae). Bioorg Med Chem. 2009;17(13):4542–7.CrossRefPubMed
11.
Hsu YL, Kuo PL, Lin CC. The proliferative inhibition and apoptotic mechanism of Saikosaponin D in human non-small cell lung cancer A549 cells. Life Sci. 2004;75(10):1231–42.CrossRefPubMed
12.
Hsu YL, Kuo PL, Chiang LC, Lin CC. Involvement of p53, nuclear factor kappaB and Fas/Fas ligand in induction of apoptosis and cell cycle arrest by saikosaponin d in human hepatoma cell lines. Cancer Lett. 2004;213(2):213–21.CrossRefPubMed
13.
Chen JC, Chang NW, Chung JG, Chen KC. Saikosaponin-A induces apoptotic mechanism in human breast MDA-MB-231 and MCF-7 cancer cells. Am J Chin Med. 2003;31(3):363–77.CrossRefPubMed
14.
Motoo Y, Sawabu N. Antitumor effects of saikosaponins, baicalin and baicalein on human hepatoma cell lines. Cancer Lett. 1994;86(1):91–5.CrossRefPubMed
15.
Liu RY, Li JP. Saikosaponin-d inhibits proliferation of human undifferentiated thyroid carcinoma cells through induction of apoptosis and cell cycle arrest. Eur Rev Med Pharmacol Sci. 2014;18(17):2435–43.PubMed
16.
Wang Q, Zheng XL, Yang L, Shi F, Gao LB, Zhong YJ, Sun H, He F, Lin Y, Wang X. Reactive oxygen species-mediated apoptosis contributes to chemosensitization effect of saikosaponins on cisplatin-induced cytotoxicity in cancer cells. J Exp Clin Cancer Res. 2010;29:159.CrossRefPubMedPubMedCentral
17.
Chen MF, Huang CC, Liu PS, Chen CH, Shiu LY. Saikosaponin a and saikosaponin d inhibit proliferation and migratory activity of rat HSC-T6 cells. J Med Food. 2013;16(9):793–800.CrossRefPubMedPubMedCentral
18.
Chen CH, Chuang HC, Huang CC, Fang FM, Huang HY, Tsai HT, Su LJ, Shiu LY, Leu S, Chien CY. Overexpression of Rap-1A indicates a poor prognosis for oral cavity squamous cell carcinoma and promotes tumor cell invasion via Aurora-A modulation. Am J Pathol. 2013;182(2):516–28.CrossRefPubMed
19.
Wang J, Chu ES, Chen HY, Man K, Go MY, Huang XR, Lan HY, Sung JJ, Yu J. microRNA-29b prevents liver fibrosis by attenuating hepatic stellate cell activation and inducing apoptosis through targeting PI3K/AKT pathway. Oncotarget. 2015;6(9):7325–38.CrossRefPubMed
20.
Chen CH, Chang AY, Li SH, Tsai HT, Shiu LY, Su LJ, Wang WL, Chiu TJ, Luo SD, Huang TL, et al. Suppression of Aurora-A-FLJ10540 signaling axis prohibits the malignant state of head and neck cancer. Mol Cancer. 2015;14:83.CrossRefPubMedPubMedCentral
21.
22.
Cao W, Cao J, Huang J, Yao J, Yan G, Xu H, Yang P. Discovery and confirmation of O-GlcNAcylated proteins in rat liver mitochondria by combination of mass spectrometry and immunological methods. PLoS One. 2013;8(10):e76399.CrossRefPubMedPubMedCentral
23.
24.
Antignani A, Youle RJ. How do Bax and Bak lead to permeabilization of the outer mitochondrial membrane? Curr Opin Cell Biol. 2006;18(6):685–9.CrossRefPubMed
25.
Belizario JE, Alves J, Occhiucci JM, Garay-Malpartida M, Sesso A. A mechanistic view of mitochondrial death decision pores. Braz J Med Biol Res. 2007;40(8):1011–24.CrossRefPubMed
26.
Bleicken S, Wagner C, Garcia-Saez AJ. Mechanistic differences in the membrane activity of Bax and Bcl-xL correlate with their opposing roles in apoptosis. Biophys J. 2013;104(2):421–31.CrossRefPubMedPubMedCentral
27.
Adachi M, Imai K. The proapoptotic BH3-only protein BAD transduces cell death signals independently of its interaction with Bcl-2. Cell Death Differ. 2002;9(11):1240–7.CrossRefPubMed
28.
Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 2001;7(3):683–94.CrossRefPubMed
29.
El Kebir D, Jozsef L, Khreiss T, Filep JG. Inhibition of K+ efflux prevents mitochondrial dysfunction, and suppresses caspase-3-, apoptosis-inducing factor-, and endonuclease G-mediated constitutive apoptosis in human neutrophils. Cell Signal. 2006;18(12):2302–13.CrossRefPubMed
30.
Jaeschke H, Bajt ML. Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci. 2006;89(1):31–41.CrossRefPubMed
Metadata
Title
Saikosaponin d induces cell death through caspase-3-dependent, caspase-3-independent and mitochondrial pathways in mammalian hepatic stellate cells
Authors
Ming-Feng Chen
S. Joseph Huang
Chao-Cheng Huang
Pei-Shan Liu
Kun-I Lin
Ching-Wen Liu
Wen-Chuan Hsieh
Li-Yen Shiu
Chang-Han Chen
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2599-0

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