Matrine‑induced apoptosis in Hep3B cells via the inhibition of MDM2

Zhou,Ning; Li,Jiequn; Li,Ting; Chen,Guangshun; Zhang,Zhongqiang; Si,Zhongzhou

doi:10.3892/mmr.2016.5999

Matrine‑induced apoptosis in Hep3B cells via the inhibition of MDM2

Authors:
- Ning Zhou
- Jiequn Li
- Ting Li
- Guangshun Chen
- Zhongqiang Zhang
- Zhongzhou Si
View Affiliations

Affiliations: Department of Organ Transplantation and General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
Published online on: December 7, 2016 https://doi.org/10.3892/mmr.2016.5999
Pages: 442-450

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Matrine, an alkaloid component derived from the Sophora root, can inhibit cancer cell proliferation and induce autophagy via p53 associated pathways. However, numerous tumor cells lack functional p53 and little is known about the effect of matrine on the p53‑deficient/mutant cancer cells. The present study aimed to assess anticancer effects of matrine in p53‑deficient human Hep3B hepatoma cells. The present results demonstrated that matrine caused Hep3B cell apoptosis by suppressing gene expression of minute double‑mutant (MDM)2. Notably, it was revealed that matrine inhibited MDM2 at the transcriptional level in a time‑ and dose‑dependent manner. This MDM2 inhibition resulted in induction of the p53 family member, p73; however, the functions of p73 were not induced since matrine‑induced p73 failed to activate its target genes, p21 and p53 upregulated modulator of apoptosis. The matrine‑induced downregulation of MDM2 led to an inhibition of inhibitor of apoptosis protein 3, which might serve a critical role in matrine‑induced apoptosis in MDM2‑overexpressing Hep3B cells. Finally, combination therapy of matrine with 100 µM epotoside successfully killed more Hep3B cells, suggesting that matrine can sensitize p53‑deficient Hep3B cells to epotoside‑induced apoptosis.

View Figures

View References

1	Hu ZL, Zhang JP, Qian DH, Lin W, Xie WF, Zhang XR and Chen WZ: Effects of matrine on mouse splenocyte proliferation and release of interleukin-1 and −6 from peritoneal macrophages in vitro. Zhongguo Yao Li Xue Bao. 17:259–261. 1996.PubMed/NCBI
2	Cheng H, Xia B, Zhang L, Zhou F, Zhang YX, Ye M, Hu ZG, Li J, Li J, Wang ZL, et al: Matrine improves 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice. Pharmacol Res. 53:202–208. 2006. View Article : Google Scholar : PubMed/NCBI
3	Liu J, Zhu M, Shi R and Yang M: Radix Sophorae flavescentis for chronic hepatitis B: A systematic review of randomized trials. Am J Chin Med. 31:337–354. 2003. View Article : Google Scholar : PubMed/NCBI
4	Tan C, Qian X, Jia R, Wu M and Liang Z: Matrine induction of reactive oxygen species activates p38 leading to caspase-dependent cell apoptosis in non-small cell lung cancer cells. Oncol Rep. 30:2529–2535. 2013.PubMed/NCBI
5	Liu XS, Jiang J, Jiao XY, Wu YE and Lin JH: Matrine-induced apoptosis in leukemia U937 cells: Involvement of caspases activation and MAPK-independent pathways. Planta Med. 72:501–506. 2006. View Article : Google Scholar : PubMed/NCBI
6	Jiang H, Hou C, Zhang S, Xie H, Zhou W, Jin Q, Cheng X, Qian R and Zhang X: Matrine upregulates the cell cycle protein E2F-1 and triggers apoptosis via the mitochondrial pathway in K562 cells. Eur J Pharmacol. 559:98–108. 2007. View Article : Google Scholar : PubMed/NCBI
7	Hu MJ, Zeng H, Wu YL, Zhang YP, Zhang S, Qiao MM and Fu H: Synergistic effects of matrine and 5-fluorouracil on tumor growth of the implanted gastric cancer in nude mice. Chin J Dig Dis. 6:68–71. 2005. View Article : Google Scholar : PubMed/NCBI
8	Zhang JQ, Li YM, Liu T, He WT, Chen YT, Chen XH, Li X, Zhou WC, Yi JF and Ren ZJ: Antitumor effect of matrine in human hepatoma G2 cells by inducing apoptosis and autophagy. World J Gastroenterol. 16:4281–4290. 2010. View Article : Google Scholar : PubMed/NCBI
9	Tanigawa S, Fujii M and Hou DX: Stabilization of p53 is involved in quercetin-induced cell cycle arrest and apoptosis in HepG2 cells. Biosci Biotechnol Biochem. 72:797–804. 2008. View Article : Google Scholar : PubMed/NCBI
10	Schavolt KL and Pietenpol JA: p53 and Delta Np63 alpha differentially bind and regulate target genes involved in cell cycle arrest, DNA repair and apoptosis. Oncogene. 26:6125–6132. 2007. View Article : Google Scholar : PubMed/NCBI
11	Reinhardt HC, Aslanian AS, Lees JA and Yaffe MB: p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell. 11:175–189. 2007. View Article : Google Scholar : PubMed/NCBI
12	Michael D and Oren M: The p53 and Mdm2 families in cancer. Curr Opin Genet Dev. 12:53–59. 2002. View Article : Google Scholar : PubMed/NCBI
13	Chène P: Inhibiting the p53-MDM2 interaction: An important target for cancer therapy. Nat Rev Cancer. 3:102–109. 2003. View Article : Google Scholar : PubMed/NCBI
14	Shiraishi T and Nielsen PE: Down-regulation of MDM2 and activation of p53 in human cancer cells by antisense 9-aminoacridine-PNA (peptide nucleic acid) conjugates. Nucleic Acids Res. 32:4893–4902. 2004. View Article : Google Scholar : PubMed/NCBI
15	Ongkeko WM, Wang XQ, Siu WY, Lau AW, Yamashita K, Harris AL, Cox LS and Poon RY: MDM2 and MDMX bind and stabilize the p53-related protein p73. Curr Biol. 9:829–832. 1999. View Article : Google Scholar : PubMed/NCBI
16	Dobbelstein M, Wienzek S, König C and Roth J: Inactivation of the p53-homologue p73 by the mdm2-oncoprotein. Oncogene. 18:2101–2106. 1999. View Article : Google Scholar : PubMed/NCBI
17	Zeng X, Chen L, Jost CA, Maya R, Keller D, Wang X, Kaelin WG Jr, Oren M, Chen J and Lu H: MDM2 suppresses p73 function without promoting p73 degradation. Mol Cell Biol. 19:3257–3266. 1999. View Article : Google Scholar : PubMed/NCBI
18	Kowalik TF, DeGregori J, Leone G, Jakoi L and Nevins JR: E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2. Cell Growth Differ. 9:113–118. 1998.PubMed/NCBI
19	Froment P, Dupont J and Christophe-Marine J: Mdm2 exerts pro-apoptotic activities by antagonizing insulin-like growth factor-I-mediated survival. Cell Cycle. 7:3098–3103. 2008. View Article : Google Scholar : PubMed/NCBI
20	Pereboom TC, van Weele LJ, Bondt A and MacInnes AW: A zebrafish model of dyskeratosis congenita reveals hematopoietic stem cell formation failure resulting from ribosomal protein-mediated p53 stabilization. Blood. 118:5458–5465. 2011. View Article : Google Scholar : PubMed/NCBI
21	Huang X, Wu Z, Mei Y and Wu M: XIAP inhibits autophagy via XIAP-Mdm2-p53 signalling. Embo J. 32:2204–2216. 2013. View Article : Google Scholar : PubMed/NCBI
22	Zheng M, Yang J, Xu X, Sebolt JT, Wang S and Sun Y: Efficacy of MDM2 inhibitor MI-219 against lung cancer cells alone or in combination with MDM2 knockdown, a XIAP inhibitor or etoposide. Anticancer Res. 30:3321–3331. 2010.PubMed/NCBI
23	Deb SP, Singh S and Deb S: MDM2 overexpression, activation of signaling networks, and cell proliferation. Subcell Biochem. 85:215–234. 2014. View Article : Google Scholar : PubMed/NCBI
24	Jones SN, Hancock AR, Vogel H, Donehower LA and Bradley A: Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci USA. 95:15608–15612. 1998. View Article : Google Scholar : PubMed/NCBI
25	Jiang Y, Zhang XY, Sun L, Zhang GL, Duerksen-Hughes P, Zhu XQ and Yang J: Methyl methanesulfonate induces apoptosis in p53-deficient H1299 and Hep3B cells through a caspase 2- and mitochondria-associated pathway. Environ Toxicol Pharmacol. 34:694–704. 2012. View Article : Google Scholar : PubMed/NCBI
26	Jiang Y, Rao K, Yang G, Chen X, Wang Q, Liu A, Zheng H and Yuan J: Benzo(a)pyrene induces p73 mRNA expression and necrosis in human lung adenocarcinoma H1299 cells. Environ Toxicol. 27:202–210. 2012. View Article : Google Scholar : PubMed/NCBI
27	Yu Q, Li Y, Mu K, Li Z, Meng Q, Wu X, Wang Y and Li L: Amplification of Mdmx and overexpression of MDM2 contribute to mammary carcinogenesis by substituting for p53 mutations. Diagn Pathol. 9:712014. View Article : Google Scholar : PubMed/NCBI
28	Chow KU, Nowak D, Boehrer S, Ruthardt M, Knau A, Hoelzer D, Mitrou PS and Weidmann E: Synergistic effects of chemotherapeutic drugs in lymphoma cells are associated with down-regulation of inhibitor of apoptosis proteins (IAPs), prostate-apoptosis-response-gene 4 (Par-4), death-associated protein (Daxx) and with enforced caspase activation. Biochem Pharmacol. 66:711–724. 2003. View Article : Google Scholar : PubMed/NCBI
29	Lederman M, Meir T, Zeschnigk M, Pe'er J and Chowers I: Inhibitor of apoptosis proteins gene expression and its correlation with prognostic factors in primary and metastatic uveal melanoma. Curr Eye Res. 33:876–884. 2008. View Article : Google Scholar : PubMed/NCBI
30	Eckelman BP, Salvesen GS and Scott FL: Human inhibitor of apoptosis proteins: Why XIAP is the black sheep of the family. EMBO Rep. 7:988–994. 2006. View Article : Google Scholar : PubMed/NCBI
31	Wang R, Li B, Wang X, Lin F, Gao P, Cheng SY and Zhang HZ: Inhibiting XIAP expression by RNAi to inhibit proliferation and enhance radiosensitivity in laryngeal cancer cell line. Auris Nasus Larynx. 36:332–339. 2009. View Article : Google Scholar : PubMed/NCBI
32	Qiao L, Li GH, Dai Y, Wang J, Li Z, Zou B, Gu Q, Ma J, Pang R, Lan HY and Wong BC: Gene expression profile in colon cancer cells with respect to XIAP expression status. Int J Colorectal Dis. 24:245–260. 2009. View Article : Google Scholar : PubMed/NCBI
33	Gu L, Zhu N, Zhang H, Durden DL, Feng Y and Zhou M: Regulation of XIAP translation and induction by MDM2 following irradiation. Cancer Cell. 15:363–375. 2009. View Article : Google Scholar : PubMed/NCBI
34	Nur-E-Kamal A, Li TK, Zhang A, Qi H, Hars ES and Liu LF: Single-stranded DNA induces ataxia telangiectasia mutant (ATM)/p53-dependent DNA damage and apoptotic signals. J Biol Chem. 278:12475–12481. 2003. View Article : Google Scholar : PubMed/NCBI
35	Sasaki Y, Morimoto I, Ishida S, Yamashita T, Imai K and Tokino T: Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: Potential application to gene therapy of colorectal cancer. Gene Ther. 8:1401–1408. 2001. View Article : Google Scholar : PubMed/NCBI
36	Blattner C, Hay T, Meek DW and Lane DP: Hypophosphorylation of Mdm2 augments p53 stability. Mol Cell Biol. 22:6170–6182. 2002. View Article : Google Scholar : PubMed/NCBI
37	Okamoto K, Li H, Jensen MR, Zhang T, Taya Y, Thorgeirsson SS and Prives C: Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol Cell. 9:761–771. 2002. View Article : Google Scholar : PubMed/NCBI