Anticancer effects of oridonin on colon cancer are mediated via BMP7/p38 MAPK/p53 signaling

Liu,Rong-Xing; Ma,Yan; Hu,Xue-Lian; Ren,Wen-Yan; Liao,Yun-Peng; Wang,Han; Zhu,Jia-Hui; Wu,Ke; He,Bai-Cheng; Sun,Wen-Juan

doi:10.3892/ijo.2018.4527

Anticancer effects of oridonin on colon cancer are mediated via BMP7/p38 MAPK/p53 signaling

Authors:
- Rong-Xing Liu
- Yan Ma
- Xue-Lian Hu
- Wen-Yan Ren
- Yun-Peng Liao
- Han Wang
- Jia-Hui Zhu
- Ke Wu
- Bai-Cheng He
- Wen-Juan Sun
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Affiliations: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China
Published online on: August 16, 2018 https://doi.org/10.3892/ijo.2018.4527
Pages: 2091-2101

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Abstract

Colon cancer is a prevalent malignancy affecting the gastrointestinal tract. Oridonin (ORI) is a promising chemotherapeutic drug used in the treatment of colon cancer. In this study, we examined the anticancer activity of ORI against colon cancer and elucidated the underlying molecular mechanisms. Cell counting kit-8, flow cytometric and western blot analyses were conducted to analyze the growth inhibitory effects of ORI on SW620 cells; we employed BMP7 and p53 recombinant adenovirus to detect the influence of ORI on the p38 MAPK signal pathway; PT-qPCR, cell immunofluorescence staining and western blot analysis were used to detect the expression of BMP7, p38 and p-p38, p53 and p-p53. A xenograft tumor model and histological evaluation were introduced to detect the effects of ORI and BMP7 in SW620 cells in vivo. ORI inhibited the proliferation of SW620 cells and induced apoptosis. ORI also increased the total and phosphorylated levels of p53. The overexpression of p53 was found to enhance the anti-proliferative effects of ORI on the SW620 cells, while the inhibition of p53 partially reversed these effects. ORI increased the expression of bone morphogenetic protein 7 (BMP7) in the SW620 cells. The overexpression of BMP7 also enhanced the antiproliferative effects of ORI on the SW620 cells and reduced the growth rate of tumors in mice. BMP7-induced immunosuppression markedly decreased the anti-proliferative effects of ORI. ORI was not found to exert any substantial effect on the phosphorylation levels of Smad1/5/8, although it increased the level of p-p38 significantly. The inhibition of p38 significantly attenuated the ORI-induced increase in the levels of p-p53. The overexpression of BMP7 enhanced the promoting effects of ORI on the p-p53 and p-p38 levels, while BMP7-induced immunosuppression reduced the effects of ORI on p-p38 and p-p53. On the whole, the findings of this study suggest that ORI may be a promising agent for use in the treatment of colon cancer, and the anticancer effects of ORI may be partially mediated through the BMP7/p38 MAPK/p53 signaling pathway.

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1	Applegate CC and Lane MA: Role of retinoids in the prevention and treatment of colorectal cancer. World J Gastrointest Oncol. 7:184–203. 2015. View Article : Google Scholar : PubMed/NCBI
2	Fellner C: Promising drugs in clinical development to treat advanced colorectal cancer. PT. 42:262–265. 2017.
3	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
4	Weaver BA: How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 25:2677–2681. 2014. View Article : Google Scholar : PubMed/NCBI
5	Owona BA and Schluesener HJ: Molecular insight in the multifunctional effects of oridonin. Drugs RD. 15:233–244. 2015. View Article : Google Scholar
6	Liu Y, Liu YZ, Zhang RX, Wang X, Meng ZJ, Huang J, Wu K, Luo JY, Zuo GW, Chen L, et al: Oridonin inhibits the proliferation of human osteosarcoma cells by suppressing Wnt/β-catenin signaling. Int J Oncol. 45:795–803. 2014. View Article : Google Scholar : PubMed/NCBI
7	Wu QX, Yuan SX, Ren CM, Yu Y, Sun WJ, He BC and Wu K: Oridonin upregulates PTEN through activating p38 MAPK and inhibits proliferation in human colon cancer cells. Oncol Rep. 35:3341–3348. 2016. View Article : Google Scholar : PubMed/NCBI
8	Lu J, Chen X, Qu S, Yao B, Xu Y, Wu J, Jin Y and Ma C: Oridonin induces G2/M cell cycle arrest and apoptosis via the PI3K/Akt signaling pathway in hormone-independent prostate cancer cells. Oncol Lett. 13:2838–2846. 2017. View Article : Google Scholar : PubMed/NCBI
9	Bollum LK, Huse K, Oksvold MP, Bai B, Hilden VI, Forfang L, Yoon SO, Wälchli S, Smeland EB and Myklebust JH: BMP-7 induces apoptosis in human germinal center B cells and is influenced by TGF-β receptor type I ALK5. PLoS One. 12:e01771882017. View Article : Google Scholar
10	Yoo HS, Kim GJ, Song DH, Chung KH, Lee KJ, Kim DH and An JH: Calcium supplement derived from Gallus gallus domesticus promotes BMP-2/RUNX2/SMAD5 and suppresses TRAP/RANK expression through MAPK signaling activation. Nutrients. 9:E5042017. View Article : Google Scholar : PubMed/NCBI
11	Bernatik O, Radaszkiewicz T, Behal M, Dave Z, Witte F, Mahl A, Cernohorsky NH, Krejci P, Stricker S and Bryja V: A novel role for the BMP antagonist noggin in sensitizing cells to non-canonical Wnt-5a/Ror2/disheveled pathway activation. Front Cell Dev Biol. 5:472017. View Article : Google Scholar : PubMed/NCBI
12	Zhang Y, Chen X, Qiao M, Zhang BQ, Wang N, Zhang Z, Liao Z, Zeng L, Deng Y, Deng F, et al: Bone morphogenetic protein 2 inhibits the proliferation and growth of human colorectal cancer cells. Oncol Rep. 32:1013–1020. 2014. View Article : Google Scholar : PubMed/NCBI
13	Basu S, Haase G and Ben-Ze'ev A: Wnt signaling in cancer stem cells and colon cancer metastasis. F1000 Res. 5:699–709. 2016. View Article : Google Scholar
14	Ren CM, Li Y, Chen QZ, Zeng YH, Shao Y, Wu QX, Yuan SX, Yang JQ, Yu Y, Wu K, et al: Oridonin inhibits the proliferation of human colon cancer cells by upregulating BMP7 to activate p38 MAPK. Oncol Rep. 35:2691–2698. 2016. View Article : Google Scholar : PubMed/NCBI
15	Briest F and Grabowski P: The p53 network as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms. Cancer Treat Rev. 41:423–430. 2015. View Article : Google Scholar : PubMed/NCBI
16	Lu L, Harutyunyan K, Jin W, Wu J, Yang T, Chen Y, Joeng KS, Bae Y, Tao J, et al: RECQL4 regulates p53 function in vivo during skeletogenesis. J Bone Miner Res. 30:1077–1089. 2015. View Article : Google Scholar : PubMed/NCBI
17	Rajeshkumar NV, Dutta P, Yabuuchi S, de Wilde RF, Martinez GV, Le A, Kamphorst JJ, Rabinowitz JD, Jain SK, Hidalgo M, et al: Therapeutic targeting of the warburg effect in pancreatic cancer relies on an absence of p53 function. Cancer Res. 75:3355–3364. 2015. View Article : Google Scholar : PubMed/NCBI
18	Inobe T, Nozaki M and Nukina N: Artificial regulation of p53 function by modulating its assembly. Biochem Biophys Res Commun. 467:322–327. 2015. View Article : Google Scholar : PubMed/NCBI
19	Gan F, Zhou Y, Hou L, Qian G, Chen X and Huang K: Ochratoxin A induces nephrotoxicity and immunotoxicity through different MAPK signaling pathways in PK15 cells and porcine primary splenocytes. Chemosphere. 182:630–637. 2017. View Article : Google Scholar : PubMed/NCBI
20	Koul HK, Pal M and Koul S: Role of p38 MAP Kinase Signal Transduction in Solid Tumors. Genes Cancer. 4:342–359. 2013. View Article : Google Scholar : PubMed/NCBI
21	Kim GT, Lee SH, Kim JI and Kim YM: Quercetin regulates the sestrin 2-AMPK-p38 MAPK signaling pathway and induces apoptosis by increasing the generation of intracellular ROS in a p53-independent manner. Int J Mol Med. 33:863–869. 2014. View Article : Google Scholar : PubMed/NCBI
22	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
23	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
24	Stayce EB, Barbara HJ, Antonio F, Jessica G, Eunice DR, Betty LC, Sherry CH, Jimmy YC and John MC: Bone morphogenetic protein signaling and growth suppression in colon cancer. Am J Physiol Gastrointest Liver Physiol. 291:G135–G145. 2006. View Article : Google Scholar
25	Carvalho C and Glynne-Jones R: Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemora-diation for rectal cancer. Lancet Oncol. 18:e354–e363. 2017. View Article : Google Scholar
26	Link KH, Coy P, Roitman M, Link C, Kornmann M and Staib L: Minimum volume discussion in the treatment of colon and rectal cancer: A review of the current status and relevance of surgeon and hospital volume regarding result quality and the impact on health economics. Visc Med. 33:140–147. 2017. View Article : Google Scholar : PubMed/NCBI
27	Li D, Han T, Liao J, Hu X, Xu S, Tian K, Gu X, Cheng K, Li Z, Hua H, et al: Oridonin, a promising ent-kaurane diterpenoid lead compound. Int J Mol Sci. 17:E13952016. View Article : Google Scholar : PubMed/NCBI
28	Xu J, Wold EA, Ding Y, Shen Q and Zhou J: Therapeutic potential of oridonin and its analogs: From anticancer and antiinflammation to neuroprotection. Molecules. 23:E4742018. View Article : Google Scholar : PubMed/NCBI
29	Wu J, Ding Y, Chen CH, Zhou Z, Ding C, Chen H, Zhou J and Chen C: A new oridonin analog suppresses triple-negative breast cancer cells and tumor growth via the induction of death receptor 5. Cancer Lett. 380:393–402. 2016. View Article : Google Scholar : PubMed/NCBI
30	Gui Z, Luo F, Yang Y, Shen C, Li S and Xu J: Oridonin inhibition and miR 200b 3p/ZEB1 axis in human pancreatic cancer. Int J Oncol. 50:111–120. 2017. View Article : Google Scholar
31	Zhang LD, Liu Z, Liu H, Ran DM, Guo JH, Jiang B, Wu YL and Gao FH: Oridonin enhances the anticancer activity of NVP-BEZ235 against neuroblastoma cells in vitro and in vivo through autophagy. Int J Oncol. 49:657–665. 2016. View Article : Google Scholar : PubMed/NCBI
32	Pi J, Jin H, Jiang J, Yang F, Cai H, Yang P, Cai J and Chen ZW: Single molecule force spectroscopy for in-situ probing oridonin inhibited ROS-mediated EGF-EGFR interactions in living KYSE-150 cells. Pharmacol Res. 119:479–489. 2017. View Article : Google Scholar : PubMed/NCBI
33	Yao Z, Xie F, Li M, Liang Z, Xu W, Yang J, Liu C, Li H, Zhou H and Qu LH: Oridonin induces autophagy via inhibition of glucose metabolism in p53-mutated colorectal cancer cells. Cell Death Dis. 8:e26332017. View Article : Google Scholar : PubMed/NCBI
34	Arvelo F, Sojo F and Cotte C: Biology of colorectal cancer. Ecancermedicalscience. 9:5202015. View Article : Google Scholar : PubMed/NCBI
35	Lochab AK and Extavour CG: Bone morphogenetic protein (BMP) signaling in animal reproductive system development and function. Dev Biol. 427:258–269. 2017. View Article : Google Scholar : PubMed/NCBI
36	Tsuji K, Cox K, Gamer L, Graf D, Economides A and Rosen V: Conditional deletion of BMP7 from the limb skeleton does not affect bone formation or fracture repair. J Orthop Res. 28:384–389. 2010.
37	Wang Z, Fu C, Chen Y, Xu F, Wang Z, Qu Z and Liu Y: FoxC2 enhances BMP7-mediated anabolism in nucleus pulposus cells of the intervertebral disc. PLoS One. 11:e01477642016. View Article : Google Scholar : PubMed/NCBI
38	Lim M, Chuong CM and Roy-Burman P: PI3K, Erk signaling in BMP7-induced epithelial-mesenchymal transition (EMT) of PC-3 prostate cancer cells in 2- and 3-dimensional cultures. Horm Cancer. 2:298–309. 2011. View Article : Google Scholar : PubMed/NCBI
39	Rodriguez-Martinez A, Alarmo EL, Saarinen L, Ketolainen J, Nousiainen K, Hautaniemi S and Kallioniemi A: Analysis of BMP4 and BMP7 signaling in breast cancer cells unveils time-dependent transcription patterns and highlights a common synexpression group of genes. BMC Med Genomics. 4:802011. View Article : Google Scholar : PubMed/NCBI
40	Buijs JT, Henriquez NV, van Overveld PG, van der Horst G, ten Dijke P and van der Pluijm G: TGF-beta and BMP7 interactions in tumour progression and bone metastasis. Clin Exp Metastasis. 24:609–617. 2007. View Article : Google Scholar : PubMed/NCBI
41	Yan P, Klingbiel D, Saridaki Z, Ceppa P, Curto M, McKee TA, Roth A, Tejpar S, Delorenzi M, Bosman FT, et al: Reduced expression of SMAD4 is associated with poor survival in colon cancer. Clin Cancer Res. 22:3037–3047. 2006. View Article : Google Scholar
42	Zhang B, Halder SK, Kashikar ND, Cho YJ, Datta A, Gorden DL and Datta PK: Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology. 138:969–980. e961–963. 2010. View Article : Google Scholar
43	Vousden KH and Lane DP: p53 in health and disease. Nat Rev Mol Cell Biol. 8:275–283. 2007. View Article : Google Scholar : PubMed/NCBI
44	Nayak D, Kumar A, Chakraborty S, Rasool RU, Amin H, Katoch A, Gopinath V, Mahajan V, Zilla MK, Rah B, et al: Inhibition of Twist1-mediated invasion by Chk2 promotes premature senescence in p53-defective cancer cells. Cell Death Differ. 24:1275–1287. 2017. View Article : Google Scholar : PubMed/NCBI