Oleanolic acid inhibits colorectal cancer angiogenesis in vivo and in vitro via suppression of STAT3 and Hedgehog pathways

Li,Li; Lin,Jiumao; Sun,Guodong; Wei,Lihui; Shen,Aling; Zhang,Mingyue; Peng,Jun

doi:10.3892/mmr.2016.5171

Oleanolic acid inhibits colorectal cancer angiogenesis in vivo and in vitro via suppression of STAT3 and Hedgehog pathways

Authors:
- Li Li
- Jiumao Lin
- Guodong Sun
- Lihui Wei
- Aling Shen
- Mingyue Zhang
- Jun Peng
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Affiliations: Department of Disease Prevention and Healthcare, Fujian Provincial Hospital, Fuzhou, Fujian 350001, P.R. China, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China, Hangzhou Naval Sanatorium of Nanjing Military Area Command, Hangzhou, Zhejiang 310002, P.R. China
Published online on: April 22, 2016 https://doi.org/10.3892/mmr.2016.5171
Pages: 5276-5282

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Abstract

Angiogenesis is an essential process of cancer progression and is regulated by multiple intracellular signaling pathways, including signal transducer and activator of transcription 3 (STAT3) and sonic hedgehog (SHH). Thus, these pathways have become a promising target for anti‑cancer therapeutic strategies. Oleanolic acid (OA) is an active compound present in various herbal medicines, which have been used historically for the clinical treatment of various types of human malignancies, including colorectal cancer (CRC). The present study used a CRC mouse xenograft model and human umbilical vein endothelial cells (HUVECs) to evaluate the effect of OA on tumor angiogenesis and on the activation of the STAT3 and SHH signaling pathways. It was determined that OA treatment significantly inhibited tumor growth and reduced intratumoral microvessel density (MVD) in CRC mice. In addition, OA treatment inhibited the proliferation, migration and tube formation in HUVECs, in a dose and time-dependent manner. Furthermore, OA markedly suppressed the activation of the STAT3 and SHH signaling pathways and inhibited the expression of the pro‑angiogenic vascular endothelial growth factor A and basic fibroblast growth factor, two important target genes of the aforementioned signaling pathways. Therefore it is suggested that inhibition of tumor angiogenesis via the suppression of multiple signaling pathways may be one of the underlying mechanisms by which OA exerts its anti-cancer effect.

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1	Folkman J: Angiogenesis. Annu Rev Med. 57:1–18. 2006. View Article : Google Scholar : PubMed/NCBI
2	Cook KM and Figg WD: Angiogenesis inhibitors: Current strategies and future prospects. CA Cancer J Clin. 60:222–243. 2010. View Article : Google Scholar : PubMed/NCBI
3	Mantovani A, Allavena P, Sica A and Balkwill F: Cancer related inflammation. Nature. 454:436–444. 2008. View Article : Google Scholar : PubMed/NCBI
4	Whiteside TL: The tumor microenvironment and its role in promoting tumor growth. Oncogene. 27:5904–5912. 2008. View Article : Google Scholar : PubMed/NCBI
5	Kerbel RS: Tumor angiogenesis. N Engl J Med. 358:2039–2049. 2008. View Article : Google Scholar : PubMed/NCBI
6	Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, Dey S and Sung B: Signal transducer and activator of transcription-3, inflammation and cancer: How intimate is the relationship? Ann NY Acad Sci. 1171:59–76. 2009. View Article : Google Scholar
7	Bromberg J and Wang TC: Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell. 15:79–80. 2009. View Article : Google Scholar : PubMed/NCBI
8	Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Inoue K, Nagayasu T and Sekine I: Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rep. 15:1445–1451. 2006.PubMed/NCBI
9	Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatikakis I, Rassidakis GZ, Zhang W, Fujio Y, Kunisada K, et al: Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: Inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol. 167:969–980. 2005. View Article : Google Scholar : PubMed/NCBI
10	Xiong H, Zhang ZG, Tian XQ, Sun DF, Liang QC, Zhang YJ, Lu R, Chen YX and Fang JY: Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest and reduces tumor cell invasion in colorectal cancer cells. Neoplasia. 10:287–297. 2008. View Article : Google Scholar : PubMed/NCBI
11	Ingham PW, Nakano Y and Seger C: Mechanisms and functions of Hedgehog signalling across the metazoa. Nat Rev Genet. 12:393–406. 2011. View Article : Google Scholar : PubMed/NCBI
12	Theunissen JW and de Sauvage FJ: Paracrine Hedgehog signaling in cancer. Cancer Res. 69:6007–6010. 2009. View Article : Google Scholar : PubMed/NCBI
13	Yoshikawa K, Shimada M, Miyamoto H, Higashijima J, Miyatani T, Nishioka M, Kurita N, Iwata T and Uehara H: Sonic hedgehog relates to colorectal carcinogenesis. J Gastroenterol. 44:1113–1117. 2009. View Article : Google Scholar : PubMed/NCBI
14	Varnat F, Duquet A, Malerba M, Zbinden M, Mas C, Gervaz P and Ruiz i Altaba A: Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med. 1:338–351. 2009. View Article : Google Scholar
15	Mazumdar T, DeVecchio J, Shi T, Jones J, Agyeman A and Houghton JA: Hedgehog signaling drives cellular survival in human colon carcinoma cells. Cancer Res. 71:1092–1102. 2011. View Article : Google Scholar :
16	Kaya M, Wada T, Akatsuka T, Kawaguchi S, Nagoya S, Shindoh M, Higashino F, Mezawa F, Okada F and Ishii S: Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clin Cancer Res. 6:572–577. 2000.PubMed/NCBI
17	Maeda K, Chung YS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T and Sowa M: Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer. 77:858–863. 1996. View Article : Google Scholar : PubMed/NCBI
18	Ferrara N, Gerber HP and LeCouter J: The biology of VEGF and its receptors. Nat Med. 9:669–676. 2003. View Article : Google Scholar : PubMed/NCBI
19	Ishigami SI, Arii S, Furutani M, Niwano M, Harada T, Mizumoto M, Mori A, Onodera H and Imamura M: Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer. 78:1379–1384. 1998. View Article : Google Scholar : PubMed/NCBI
20	Gille H, Kowalski J, Li B, LeCouter J, Moffat B, Zioncheck TF, Pelletier N and Ferrara N: Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. Biol Chem. 276:3222–3230. 2001. View Article : Google Scholar
21	Gordaliza M: Natural products as leads to anticancer drugs. Clin Transl Oncol. 9:767–776. 2007. View Article : Google Scholar : PubMed/NCBI
22	Newman DJ, Cragg GM and Snader KM: The influence of natural products upon drug discovery. Nat Prod Rep. 17:215–234. 2000. View Article : Google Scholar : PubMed/NCBI
23	Yang G, Li X, Li X, Wang L, Li J, Song X, Chen J, Guo Y, Sun X, Wang S, et al: Traditional chinese medicine in cancer care: A review of case series published in the Chinese literature. Evid Based Complement Alternat Med. 2012:7510462012. View Article : Google Scholar : PubMed/NCBI
24	Wei L, Lin J, Wu G, Xu W, Li H, Hong Z and Peng J: Scutellaria barbata D. Don induces G1/S arrest via modulation of p53 and Akt pathways in human colon carcinoma cells. Oncol Rep. 29:1623–1628. 2013.PubMed/NCBI
25	Lin J, Wei L, Shen A, Cai Q, Xu W, Li H, Zhan Y, Hong Z and Peng J: Hedyotis diffusa Willd extract suppresses Sonic hedgehog signaling leading to the inhibition of colorectal cancer angiogenesis. Int J Oncol. 42:651–656. 2013. View Article : Google Scholar : PubMed/NCBI
26	Cai Q, Lin J, Wei L, Zhang L, Wang L, Zhan Y, Zeng J, Xu W, Shen A, Hong Z and Peng J: Hedyotis diffusa Willd inhibits colorectal cancer growth in vivo via inhibition of STAT3 signaling pathway. Int J Mol Sci. 13:6117–6128. 2012. View Article : Google Scholar : PubMed/NCBI
27	Peng J, Chen Y, Lin J, Zhuang Q, Xu W, Hong Z and Sferra TJ: Patrinia scabiosaefolia extract suppresses proliferation and promotes apoptosis by inhibiting the STAT3 pathway in human multiple myeloma cells. Mol Med Rep. 4:313–318. 2011.PubMed/NCBI
28	Wang X, Bai H, Zhang X, Liu J, Cao P, Liao N, Zhang W, Wang Z and Hai C: Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell cycle arrest and mitochondrial-dependent apoptosis. Carcinogenesis. 34:1323–1330. 2013. View Article : Google Scholar : PubMed/NCBI
29	Lúcio KA, Rocha Gda G, Monção-Ribeiro LC, Fernandes J, Takiya CM and Gattass CR: Oleanolic acid initiates apoptosis in non-small cell lung cancer cell lines and reduces metastasis of a B16F10 melanoma model in vivo. PLoS One. 6:e285962011. View Article : Google Scholar : PubMed/NCBI
30	Wei J, Liu M, Liu H, Wang H, Wang F, Zhang Y, Han L and Lin X: Oleanolic acid arrests cell cycle and induces apoptosis via ROS-mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells. J Appl Toxicol. 33:756–765. 2013. View Article : Google Scholar
31	Institute of Laboratory Animal Resources (US); Committee on Care, Use of Laboratory Animals, and National Institutes of Health (US); Division of Research Resources: Guide for the care and use of laboratory animals. 8th edition. National Academies Press; Washington, DC: 2011
32	Siegel R, Desantis C and Jemal A: Colorectal cancer statistics, 2014. CA Cancer J Clin. 64:104–117. 2014. View Article : Google Scholar : PubMed/NCBI
33	Markowitz SD and Bertagnolli MM: Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med. 361:2449–2460. 2009. View Article : Google Scholar : PubMed/NCBI
34	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI
35	Lippman SM: The dilemma and promise of cancer chemoprevention. Nat Clin Pract Oncol. 3:5232006. View Article : Google Scholar : PubMed/NCBI
36	Longley DB, Allen WL and Johnston PG: Drug resistance, predictive markers and pharmacogenomics in colorectal cancer. Biochim Biophys Acta. 1766:184–196. 2006.PubMed/NCBI