Oridonin upregulates PTEN through activating p38 MAPK and inhibits proliferation in human colon cancer cells

Wu,Qiu-Xiang; Yuan,Shuang-Xue; Ren,Chun-Mei; Yu,Yu; Sun,Wen-Juan; He,Bai-Cheng; Wu,Ke

doi:10.3892/or.2016.4735

Oridonin upregulates PTEN through activating p38 MAPK and inhibits proliferation in human colon cancer cells

Authors:
- Qiu-Xiang Wu
- Shuang-Xue Yuan
- Chun-Mei Ren
- Yu Yu
- Wen-Juan Sun
- Bai-Cheng He
- Ke Wu
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Affiliations: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China
Published online on: April 7, 2016 https://doi.org/10.3892/or.2016.4735
Pages: 3341-3348

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Abstract

Oridonin (ORI) has been reported as an antiproliferation and apoptosis-inducing natural product in various cancer cells. However, the exact molecular mechanism underlying these effects remains unclear. In the present study, we demonstrated the antiproliferation effect of ORI in HCT116 cells, and analyzed the possible molecular mechanism which mediates this effect. We found that ORI inhibits proliferation, induces cell cycle arrest and apoptosis in HCT116 cells, thus also tumor growth. Mechanically, we found that ORI has no substantial effect on mRNA expression of phosphatase and tensin homologue (PTEN), but increases the total protein level of PTEN and markedly reduces the phosphorylation of PTEN; Exogenous expression of PTEN potentiates the anticancer effect of ORI, while knockdown of PTEN attenuates it. ORI also increases the phosphorylation of p38 MAPK, and p38 MAPK-specific inhibitor reduces the antiproliferation effect ORI in HCT116 cells. Moreover, inhibition of p38 MAPK increases the phosphorylation of PTEN, and reverses ORI-induced decrease of PTEN phosphorylation. Our findings suggested that ORI may be a potential anticancer drug for colon cancer, this effect may be mediated by enhancing the function of PTEN through reducing its phosphorylation, which may be resulted from the ORI-induced activation of p38 MAPK.

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1	Chemotherapy of metastatic colorectal cancer. Prescrire Int. 19:219–224. 2010.PubMed/NCBI
2	Tran NH, Cavalcante LL, Lubner SJ, Mulkerin DL, LoConte NK, Clipson L, Matkowskyj KA and Deming DA: Precision medicine in colorectal cancer: The molecular profile alters treatment strategies. Ther Adv Med Oncol. 7:252–262. 2015. View Article : Google Scholar : PubMed/NCBI
3	Binefa G, Rodríguez-Moranta F, Teule A and Medina-Hayas M: Colorectal cancer: From prevention to personalized medicine. World J Gastroenterol. 20:6786–6808. 2014. View Article : Google Scholar : PubMed/NCBI
4	Feng QY, Wei Y, Chen JW, Chang WJ, Ye LC, Zhu DX and Xu JM: Anti-EGFR and anti-VEGF agents: Important targeted therapies of colorectal liver metastases. World J Gastroenterol. 20:4263–4275. 2014. View Article : Google Scholar : PubMed/NCBI
5	Banjerdpongchai R, Chanwikruy Y, Rattanapanone V and Sripanidkulchai B: Induction of apoptosis in the human Leukemic U937 cell line by Kaempferia parviflora Wall.ex.Baker extract and effects of paclitaxel and camptothecin. Asian Pac J Cancer Prev. 10:1137–1140. 2009.PubMed/NCBI
6	Weaver BA: How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 25:2677–2681. 2014. View Article : Google Scholar : PubMed/NCBI
7	Zhu Y, Xie L, Chen G, Wang H and Zhang R: Effects of oridonin on proliferation of HT29 human colon carcinoma cell lines both in vitro and in vivo in mice. Pharmazie. 62:439–444. 2007.PubMed/NCBI
8	Liu YQ, Mu ZQ, You S, Tashiro S, Onodera S and Ikejima T: Fas/FasL signaling allows extracelluar-signal regulated kinase to regulate cytochrome c release in oridonin-induced apoptotic U937 cells. Biol Pharm Bull. 29:1873–1879. 2006. View Article : Google Scholar : PubMed/NCBI
9	Hsieh TC, Wijeratne EK, Liang JY, Gunatilaka AL and Wu JM: Differential control of growth, cell cycle progression, and expression of NF-kappaB in human breast cancer cells MCF-7, MCF-10A, and MDA-MB-231 by ponicidin and oridonin, diterpenoids from the Chinese herb Rabdosia rubescens. Biochem Biophys Res Commun. 337:224–231. 2005. View Article : Google Scholar : PubMed/NCBI
10	Zhou GB, Kang H, Wang L, Gao L, Liu P, Xie J, Zhang FX, Weng XQ, Shen ZX, Chen J, et al: Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. Blood. 109:3441–3450. 2007. View Article : Google Scholar : PubMed/NCBI
11	Hu HZ, Yang YB, Xu XD, Shen HW, Shu YM, Ren Z, Li XM, Shen HM and Zeng HT: Oridonin induces apoptosis via PI3K/Akt pathway in cervical carcinoma HeLa cell line. Acta Pharmacol Sin. 28:1819–1826. 2007. View Article : Google Scholar : PubMed/NCBI
12	Gao FH, Liu F, Wei W, Liu LB, Xu MH, Guo ZY, Li W, Jiang B and Wu YL: Oridonin induces apoptosis and senescence by increasing hydrogen peroxide and glutathione depletion in colorectal cancer cells. Int J Mol Med. 29:649–655. 2012.PubMed/NCBI
13	Cheng Y, Qiu F, Ye YC, Tashiro S, Onodera S and Ikejima T: Oridonin induces G₂/M arrest and apoptosis via activating ERK-p53 apoptotic pathway and inhibiting PTK-Ras-Raf-JNK survival pathway in murine fibrosarcoma L929 cells. Arch Biochem Biophys. 490:70–75. 2009. View Article : Google Scholar : PubMed/NCBI
14	Bu HQ, Liu DL, Wei WT, Chen L, Huang H, Li Y and Cui JH: Oridonin induces apoptosis in SW1990 pancreatic cancer cells via p53- and caspase-dependent induction of p38 MAPK. Oncol Rep. 31:975–982. 2014.
15	Luo J, Deng ZL, Luo X, Tang N, Song WX, Chen J, Sharff KA, Luu HH, Haydon RC, Kinzler KW, et al: A protocol for rapid generation of recombinant adenoviruses using the AdEasy system. Nat Protoc. 2:1236–1247. 2007. View Article : Google Scholar : PubMed/NCBI
16	Wu K, Zhou M, Wu QX, Yuan SX, Wang DX, Jin JL, Huang J, Yang JQ, Sun WJ, Wan LH, et al: The role of IGFBP-5 in mediating the anti-proliferation effect of tetrandrine in human colon cancer cells. Int J Oncol. 46:1205–1213. 2015.
17	He BC, Gao JL, Zhang BQ, Luo Q, Shi Q, Kim SH, Huang E, Gao Y, Yang K, Wagner ER, et al: Tetrandrine inhibits Wnt/β-catenin signaling and suppresses tumor growth of human colorectal cancer. Mol Pharmacol. 79:211–219. 2011. View Article : Google Scholar :
18	Owona BA and Schluesener HJ: Molecular insight in the multifunctional effects of oridonin. Drugs RD. 15:233–244. 2015. View Article : Google Scholar
19	Wang S, Zhong Z, Wan J, Tan W, Wu G, Chen M and Wang Y: Oridonin induces apoptosis, inhibits migration and invasion on highly-metastatic human breast cancer cells. Am J Chin Med. 41:177–196. 2013. View Article : Google Scholar : PubMed/NCBI
20	Liu DL, Bu HQ, Jin HM, Zhao JF, Li Y and Huang H: Enhancement of the effects of gemcitabine against pancreatic cancer by oridonin via the mitochondrial caspase-dependent signaling pathway. Mol Med Rep. 10:3027–3034. 2014.PubMed/NCBI
21	Liu Y, Liu JH, Chai K, Tashiro S, Onodera S and Ikejima T: Inhibition of c-Met promoted apoptosis, autophagy and loss of the mitochondrial transmembrane potential in oridonin-induced A549 lung cancer cells. J Pharm Pharmacol. 65:1622–1642. 2013. View Article : Google Scholar : PubMed/NCBI
22	Gao SY, Li J, Qu XY, Zhu N and Ji YB: Downregulation of Cdk1 and cyclinB1 expression contributes to oridonin-induced cell cycle arrest at G2/M phase and growth inhibition in SGC-7901 gastric cancer cells. Asian Pac J Cancer Prev. 15:6437–6441. 2014. View Article : Google Scholar : PubMed/NCBI
23	Li X, Li X, Wang J, Ye Z and Li JC: Oridonin up-regulates expression of P21 and induces autophagy and apoptosis in human prostate cancer cells. Int J Biol Sci. 8:901–912. 2012. View Article : Google Scholar : PubMed/NCBI
24	Gao FH, Hu XH, Li W, Liu H, Zhang YJ, Guo ZY, Xu MH, Wang ST, Jiang B, Liu F, et al: Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc. BMC Cancer. 10:6102010. View Article : Google Scholar : PubMed/NCBI
25	Cui Q, Tashiro S, Onodera S, Minami M and Ikejima T: Oridonin induced autophagy in human cervical carcinoma HeLa cells through Ras, JNK, and P38 regulation. J Pharmacol Sci. 105:317–325. 2007. View Article : Google Scholar : PubMed/NCBI
26	Feng FF, Zhang DR, Tian KL, Lou HY, Qi XL, Wang YC, Duan CX, Jia LJ, Wang FH, Liu Y, et al: Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by oridonin nanosuspension. Drug Deliv. 18:265–271. 2011. View Article : Google Scholar
27	Li D, Wu LJ, Tashiro S, Onodera S and Ikejima T: Oridonin induces human epidermoid carcinoma A431 cell apoptosis through tyrosine kinase and mitochondrial pathway. J Asian Nat Prod Res. 10:77–87. 2008. View Article : Google Scholar
28	Huang HL, Weng HY, Wang LQ, Yu CH, Huang QJ, Zhao PP, Wen JZ, Zhou H and Qu LH: Triggering Fbw7-mediated proteasomal degradation of c-Myc by oridonin induces cell growth inhibition and apoptosis. Mol Cancer Ther. 11:1155–1165. 2012. View Article : Google Scholar : PubMed/NCBI
29	Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and González-Barón M: PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30:193–204. 2004. View Article : Google Scholar : PubMed/NCBI
30	Osaki M, Oshimura M and Ito H: PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis. 9:667–676. 2004. View Article : Google Scholar : PubMed/NCBI
31	Polivka J Jr and Janku F: Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 142:164–175. 2014. View Article : Google Scholar
32	Carnero A, Blanco-Aparicio C, Renner O, Link W and Leal JF: The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets. 8:187–198. 2008. View Article : Google Scholar : PubMed/NCBI
33	Milella M, Falcone I, Conciatori F, Cesta Incani U, Del Curatolo A, Inzerilli N, Nuzzo CM, Vaccaro V, Vari S, Cognetti F, et al: PTEN: Multiple functions in human malignant tumors. Front Oncol. 5:242015. View Article : Google Scholar : PubMed/NCBI
34	Waniczek D, Śnietura M, Młynarczyk-Liszka J, Pigłowski W, Kopeć A, Lange D, Rudzki M and Arendt J: PTEN expression profiles in colorectal adenocarcinoma and its precancerous lesions. Pol J Pathol. 64:15–20. 2013. View Article : Google Scholar : PubMed/NCBI
35	Hsu CP, Kao TY, Chang WL, Nieh S, Wang HL and Chung YC: Clinical significance of tumor suppressor PTEN in colorectal carcinoma. Eur J Surg Oncol. 37:140–147. 2011. View Article : Google Scholar : PubMed/NCBI
36	Song MS, Salmena L and Pandolfi PP: The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 13:283–296. 2012.PubMed/NCBI
37	Tormos AM, Taléns-Visconti R, Nebreda AR and Sastre J: p38 MAPK: A dual role in hepatocyte proliferation through reactive oxygen species. Free Radic Res. 47:905–916. 2013. View Article : Google Scholar : PubMed/NCBI
38	Cui Q, Tashiro S, Onodera S, Minami M and Ikejima T: Autophagy preceded apoptosis in oridonin-treated human breast cancer MCF-7 cells. Biol Pharm Bull. 30:859–864. 2007. View Article : Google Scholar : PubMed/NCBI
39	Huang J, Yuan SX, Wang DX, Wu QX, Wang X, Pi CJ, Zou X, Chen L, Ying LJ, Wu K, et al: The role of COX-2 in mediating the effect of PTEN on BMP9 induced osteogenic differentiation in mouse embryonic fibroblasts. Biomaterials. 35:9649–9659. 2014. View Article : Google Scholar : PubMed/NCBI