Pristimerin induces apoptosis of oral squamous cell carcinoma cells via G1 phase arrest and MAPK/Erk1/2 and Akt signaling inhibition

Wu,Haiyan; Li,Long; Ai,Zhengdong; Yin,Jingyi; Chen,Li

doi:10.3892/ol.2019.9903

Pristimerin induces apoptosis of oral squamous cell carcinoma cells via G1 phase arrest and MAPK/Erk1/2 and Akt signaling inhibition

Authors:
- Haiyan Wu
- Long Li
- Zhengdong Ai
- Jingyi Yin
- Li Chen
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Affiliations: Department of Pathophysiology, Medical School, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China, Department of Stomatology, Shekou People's Hospital, Shenzhen, Guangdong 518067, P.R. China
Published online on: January 8, 2019 https://doi.org/10.3892/ol.2019.9903
Pages: 3017-3025

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Abstract

Pristimerin is an active compound isolated from the traditional Chinese herbs Celastraceae and Hippocrateaceae. It has been reported to exert antitumor effects under experimental and clinical conditions; however, the antitumor effects and underlying mechanisms of pristimerin in oral cancer cells have not yet been identified. In the present study, the anticancer potential of pristimerin was investigated in two oral squamous cell carcinoma (OSCC) cell lines, CAL‑27 and SCC‑25. Results demonstrated that pristimerin was toxic against the two cell lines, and exhibited inhibitory effects against proliferation. Furthermore, pristimerin exhibited a more potent anti‑proliferative activity in CAL‑27 and SCC‑25 cells than the common chemotherapy drugs cisplatin and 5‑fluorouracil. In addition, cell cycle distribution analysis revealed that G0/G1 phase arrest was induced following pristimerin treatment in CAL‑27 and SCC‑25 cells, which was strongly associated with upregulation of p21 and p27, coupled with downregulation of cyclin D1 and cyclin E. Meanwhile, pristimerin induced significant apoptosis of CAL‑27 and SCC‑25 cells, alongside decreased levels of caspase‑3 and specific cleavage of poly (ADP‑ribose) polymerase. These effects were associated with inhibition of the mitogen‑activated protein kinase/extracellular signal‑regulated kinase 1/2 and protein kinase B signaling pathways. With regards to these results, pristimerin may be considered a potent novel active substance for the treatment of OSCC.

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1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
2	Guha N, Warnakulasuriya S, Vlaanderen J and Straif K: Betel quid chewing and the risk of oral and oropharyngeal cancers: A meta-analysis with implications for cancer control. Int J Cancer. 135:1433–1443. 2014. View Article : Google Scholar : PubMed/NCBI
3	Pednekar MS, Gupta PC, Yeole BB and Hebert JR: Association of tobacco habits, including bidi smoking, with overall and site-specific cancer incidence: Results from the Mumbai cohort study. Cancer Causes Control. 22:859–868. 2011. View Article : Google Scholar : PubMed/NCBI
4	Radoï L and Luce D: A review of risk factors for oral cavity cancer: The importance of a standardized case definition. Community Dent Oral Epidemiol. 41:97–109, e178-e191. 2013. View Article : Google Scholar : PubMed/NCBI
5	Wikner J, Gröbe A, Pantel K and Riethdorf S: Squamous cell carcinoma of the oral cavity and circulating tumour cells. World J Clin Oncol. 5:114–124. 2014. View Article : Google Scholar : PubMed/NCBI
6	Newman DJ, Cragg GM and Snader KM: Natural products as sources of new drugs over the period 1981–2002. J Nat Prod. 66:1022–1037. 2003. View Article : Google Scholar : PubMed/NCBI
7	Brinker AM, Ma J, Lipsky PE and Raskin I: Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae). Phytochemistry. 68:732–766. 2007. View Article : Google Scholar : PubMed/NCBI
8	Gao JM, Wu WJ, Zhang JW and Konishi Y: The dihydro-beta-agarofuran sesquiterpenoids. Nat Prod Rep. 24:1153–1189. 2007. View Article : Google Scholar : PubMed/NCBI
9	Salminen A, Lehtonen M, Suuronen T, Kaarniranta K and Huuskonen J: Terpenoids: Natural inhibitors of NF-kappaB signaling with anti-inflammatory and anticancer potential. Cell Mol Life Sci. 65:2979–2999. 2008. View Article : Google Scholar : PubMed/NCBI
10	Tiedemann RE, Schmidt J, Keats JJ, Shi CX, Zhu YX, Palmer SE, Mao X, Schimmer AD and Stewart AK: Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-kappaB with antimyeloma activity in vitro and in vivo. Blood. 113:4027–4037. 2009. View Article : Google Scholar : PubMed/NCBI
11	Wu CC, Chan ML, Chen WY, Tsai CY, Chang FR and Wu YC: Pristimerin induces caspase-dependent apoptosis in MDA-MB-231 cells via direct effects on mitochondria. Mol Cancer Ther. 4:1277–1285. 2005. View Article : Google Scholar : PubMed/NCBI
12	Guo Y, Zhang W, Yan YY, Ma CG, Wang X, Wang C and Zhao JL: Triterpenoid pristimerin induced HepG2 cells apoptosis through ROS-mediated mitochondrial dysfunction. J BUON. 18:477–485. 2013.PubMed/NCBI
13	Deeb D, Gao X, Liu YB, Pindolia K and Gautam SC: Pristimerin, a quinonemethide triterpenoid, induces apoptosis in pancreatic cancer cells through the inhibition of pro-survival Akt/NF-kappaB/mTOR signaling proteins and anti-apoptotic Bcl-2. Int J Oncol. 44:1707–1715. 2014. View Article : Google Scholar : PubMed/NCBI
14	Liu YB, Gao X, Deeb D, Arbab AS and Gautam SC: Pristimerin induces apoptosis in prostate cancer cells by down-regulating Bcl-2 through ROS-dependent Ubiquitin-proteasomal degradation pathway. J Carcinog Mutagen Suppl. 6:0052013.
15	Byun JY, Kim MJ, Eum DY, Yoon CH, Seo WD, Park KH, Hyun JW, Lee YS, Lee JS, Yoon MY and Lee SJ: Reactive oxygen species-dependent activation of Bax and poly(ADP-ribose) polymerase-1 is required for mitochondrial cell death induced by triterpenoid pristimerin in human cervical cancer cells. Mol Pharmacol. 76:734–744. 2009. View Article : Google Scholar : PubMed/NCBI
16	Lu Z, Jin Y, Chen C, Li J, Cao Q and Pan J: Pristimerin induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation by blocking NF-kappaB signaling and depleting Bcr-Abl. Mol Cancer. 9:1122010. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Call JA, Eckhardt SG and Camidge DR: Targeted manipulation of apoptosis in cancer treatment. Lancet. Oncol. 9:1002–1011. 2008.
19	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
20	Molinari M: Cell cycle checkpoints and their inactivation in human cancer. Cell Prolif. 33:261–274. 2000. View Article : Google Scholar : PubMed/NCBI
21	Nakanishi M, Shimada M and Niida H: Genetic instability in cancer cells by impaired cell cycle checkpoints. Cancer Sci. 97:984–989. 2006. View Article : Google Scholar : PubMed/NCBI
22	Ball KL: p21: Structure and functions associated with cyclin-CDK binding. Prog Cell Cycle Res. 3:125–134. 1997. View Article : Google Scholar : PubMed/NCBI
23	Castedo M, Perfettini JL, Roumier T and Kroemer G: Cyclin-dependent kinase-1: Linking apoptosis to cell cycle and mitotic catastrophe. Cell Death Differ. 9:1287–1293. 2002. View Article : Google Scholar : PubMed/NCBI
24	Guo H, Ray RM and Johnson LR: RhoA stimulates IEC-6 cell proliferation by increasing polyamine-dependent Cdk2 activity. Am J Physiol Gastrointest Liver Physiol. 285:G704–G713. 2003. View Article : Google Scholar : PubMed/NCBI
25	Sherr CJ and Roberts JM: Living with or without cyclins and cyclin-dependent kinases. Genes Dev. 18:2699–2711. 2004. View Article : Google Scholar : PubMed/NCBI
26	Lee JS, Yoon IS, Lee MS, Cha EY, Thuong PT, Diep TT and Kim JR: Anticancer activity of pristimerin in epidermal growth factor receptor 2-positive SKBR3 human breast cancer cells. Biol Pharm Bull. 36:316–325. 2013. View Article : Google Scholar : PubMed/NCBI
27	Yousef BA, Guerram M, Hassan HM, Hamdi AM, Zhang LY and Jiang ZZ: Pristimerin demonstrates anticancer potential in colorectal cancer cells by inducing G1 phase arrest and apoptosis and suppressing various pro-survival signaling proteins. Oncol Rep. 35:1091–1100. 2016. View Article : Google Scholar : PubMed/NCBI
28	Wang WH, Hsuan KY, Chu LY, Lee CY, Tyan YC, Chen ZS and Tsai WC: Anticancer effects of Salvia miltiorrhiza alcohol extract on oral squamous carcinoma cells. Evid Based Complement Alternat Med. 2017:53640102017. View Article : Google Scholar : PubMed/NCBI
29	Yan YY, Bai JP, Xie Y, Yu JZ and Ma CG: The triterpenoid pristimerin induces U87 glioma cell apoptosis through reactive oxygen species-mediated mitochondrial dysfunction. Oncol Lett. 5:242–248. 2013. View Article : Google Scholar : PubMed/NCBI
30	Eum DY, Byun JY, Yoon CH, Seo WD, Park KH, Lee JH, Chung HY, An S, Suh Y, Kim MJ and Lee SJ: Triterpenoid pristimerin synergizes with taxol to induce cervical cancer cell death through reactive oxygen species-mediated mitochondrial dysfunction. Anticancer Drugs. 22:763–773. 2011. View Article : Google Scholar : PubMed/NCBI
31	Wang Y, Zhou Y, Zhou H, Jia G, Liu J, Han B, Cheng Z, Jiang H, Pan S and Sun B: Pristimerin causes G1 arrest, induces apoptosis, and enhances the chemosensitivity to gemcitabine in pancreatic cancer cells. PLoS One. 7:e438262012. View Article : Google Scholar : PubMed/NCBI
32	Ba XH, Cai LP and Han W: Effect of cilostazol pretreatment on the PARP/AIF-mediated apoptotic pathway in rat cerebral ischemia-reperfusion models. Exp Ther Med. 7:1209–1214. 2014. View Article : Google Scholar : PubMed/NCBI
33	Wan Y, Xin Y, Zhang C, Wu D, Ding D, Tang L, Owusu L, Bai J and Li W: Fermentation supernatants of Lactobacillus delbrueckii inhibit growth of human colon cancer cells and induce apoptosis through a caspase 3-dependent pathway. Oncol Lett. 7:1738–1742. 2014. View Article : Google Scholar : PubMed/NCBI
34	Cantrell DA: Phosphoinositide 3-kinase signalling pathways. J Cell Sci. 114:1439–1445. 2001.PubMed/NCBI
35	Liu Z, Zhu G, Getzenberg RH and Veltri RW: The upregulation of PI3K/Akt and MAP kinase pathways is associated with resistance of microtubule-targeting drugs in prostate cancer. J Cell Biochem. 116:1341–1349. 2015. View Article : Google Scholar : PubMed/NCBI
36	McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, et al: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 1773:1263–1284. 2007. View Article : Google Scholar : PubMed/NCBI
37	Xie G, Yu X, Liang H, Chen J, Tang X, Wu S and Liao C: Pristimerin overcomes adriamycin resistance in breast cancer cells through suppressing Akt signaling. Oncol Lett. 11:3111–3116. 2016. View Article : Google Scholar : PubMed/NCBI