Ursolic acid promotes colorectal cancer cell apoptosis and inhibits cell proliferation via modulation of multiple signaling pathways

Lin,Jiumao; Chen,Youqin; Wei,Lihui; Shen,Aling; Sferra,Thomas J.; Hong,Zhenfeng; Peng,Jun

doi:10.3892/ijo.2013.2040

Ursolic acid promotes colorectal cancer cell apoptosis and inhibits cell proliferation via modulation of multiple signaling pathways

Authors:
- Jiumao Lin
- Youqin Chen
- Lihui Wei
- Aling Shen
- Thomas J. Sferra
- Zhenfeng Hong
- Jun Peng
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Affiliations: Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA
Published online on: July 26, 2013 https://doi.org/10.3892/ijo.2013.2040
Pages: 1235-1243

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Abstract

The development of colorectal cancer (CRC) is strongly correlated with the aberrant activation of multiple intracellular signaling transduction cascades including STAT3, ERK, JNK and p38 pathways which usually function redundantly. In addition, crosstalk between these pathways forms a complicated signaling network that is regulated by compensatory mechanisms. Therefore, most of the currently used and single-target-based antitumor agents might not always be therapeutically effective. Moreover, long-term use of these agents often generates drug resistance. These problems highlight the urgent need for the development of novel anticancer chemotherapies. Ursolic acid (UA) is a major active compound present in many medicinal herbs that have long been used for the clinical treatment of CRC. Although previous studies have demonstrated an antitumor effect for UA, the precise mechanisms of its tumoricidal activity are not well understood. In the present study, using CRC mouse xenograft model and the HT-29 human colon carcinoma cell line, we evaluated the efficacy of UA against tumor growth in vivo and in vitro and investigated the underlying molecular mechanisms. We found that UA inhibits cancer growth without apparent toxicity. Furthermore, UA significantly suppresses the activation of several CRC-related signaling pathways and alters the expression of critical target genes. These molecular effects lead to the induction of apoptosis and inhibition of cellular proliferation. These data demonstrate that UA possesses a broad range of anticancer activities due to its ability to affect multiple intracellular targets, suggesting that UA could be a novel multipotent therapeutic agent for cancer treatment.

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1.	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2.	Gustin DM and Brenner DE: Chemoprevention of colon cancer: current status and future prospects. Cancer Metastasis Rev. 21:323–348. 2002. View Article : Google Scholar : PubMed/NCBI
3.	Gorlick R and Bertino JR: Drug resistance in colon cancer. Semin Oncol. 26:606–611. 1999.
4.	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
5.	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 : PubMed/NCBI
6.	Zhong Z, Wen Z and Darnell J: Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 264:95–98. 1994. View Article : Google Scholar : PubMed/NCBI
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, Hamilton SR and Amin HM: 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 Z, Tian X, Sun D, Liang Q, Zhang Y, Lu R, Chen Y and Fang J: 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.PubMed/NCBI
11.	Sebolt-Leopold JS: Development of anticancer drugs targeting the MAP kinase pathway. Oncogene. 19:6594–6599. 2000. View Article : Google Scholar : PubMed/NCBI
12.	Seger R and Krebs EG: The MAPK signaling cascade. FASEB J. 9:726–735. 1995.PubMed/NCBI
13.	Taupin D and Podolski DK: Mitogen-activated protein kinase activation regulates intestinal epithelial differentiation. Gastroenterology. 116:1072–1080. 1999. View Article : Google Scholar : PubMed/NCBI
14.	Wang X, Wang Q, Hu W and Evers BM: Regulation of phorbol estermediated TRAF1 induction in human colon cancer cells through a PKC/RAF/ERK/NF-kappaB-dependent pathway. Oncogene. 23:1885–1895. 2004. View Article : Google Scholar : PubMed/NCBI
15.	Roberts PJ and Der CJ: Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 26:3291–3310. 2007. View Article : Google Scholar : PubMed/NCBI
16.	Schwartsmann G, Di Leone LP, Dal Pizzol F and Roesler R: MAPK pathway activation in colorectal cancer: a therapeutic opportunity for GRP receptor antagonists. Lancet Oncol. 6:444–445. 2005. View Article : Google Scholar : PubMed/NCBI
17.	Fang JY and Richardson BC: The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 6:322–327. 2005. View Article : Google Scholar : PubMed/NCBI
18.	Ma XH and Wang ZW: Anticancer drug discovery in the future: an evolutionary perspective. Drug Discov Today. 14:1136–1142. 2009. View Article : Google Scholar : PubMed/NCBI
19.	Gordaliza M: Natural products as leads to anticancer drugs. Clin Transl Oncol. 9:767–776. 2007. View Article : Google Scholar : PubMed/NCBI
20.	Lin JM, Chen YQ, Wei LH, Chen XZ, Xu W, Hong ZF, Sferra TJ and Peng J: Hedyotis Diffusa Willd extract induces apoptosis via activation of the mitochondrion-dependent pathway in human colon carcinoma cells. Int J Oncol. 37:1331–1338. 2010.
21.	Cai QY, Lin JM, Wei LH, Zhang L, Wang LL, Zhan YZ, Zeng JW, Xu W, Shen AL, Hong ZF 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
22.	Wei LH, Chen YQ, Lin JM, Zhao JY, Chen XZ, Xu W, Liu XX, Sferra TJ and Peng J: Scutellaria Barbata D. Don induces apoptosis of human colon carcinoma cell via activation of the mitochondrion-dependent pathway. J Med Plants Res. 5:1962–1970. 2011.
23.	Zheng LP, Chen YQ, Lin W, Zhuang QC, Chen XZ, Xu W, Liu XX, Peng J and Sferra TJ: Spica Prunellae extract promotes mitochondrion-dependent apoptosis in a human colon carcinoma cell line. Afr J Pharm Pharmacol. 5:327–335. 2011. View Article : Google Scholar
24.	Ikeda Y, Murakami A and Ohigashi H: Ursolic acid: an anti- and pro-inflammatory triterpenoid. Mol Nutr Food Res. 52:26–42. 2008. View Article : Google Scholar : PubMed/NCBI
25.	Xavier CP, Lima CF, Preto A, Seruca R, Fernandes-Ferreira M and Pereira-Wilson C: Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells. Cancer Lett. 281:162–170. 2009. View Article : Google Scholar : PubMed/NCBI
26.	Andersson D, Liu JJ, Nilsson A and Duan RD: Ursolic acid inhibits proliferation and stimulates apoptosis in HT29 cells following activation of alkaline sphingomyelinase. Anticancer Res. 23:3317–3322. 2003.PubMed/NCBI
27.	Adams J and Cory S: The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 26:1324–1337. 2007. View Article : Google Scholar : PubMed/NCBI
28.	Youle RJ and Strasser A: The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 9:47–59. 2008. View Article : Google Scholar : PubMed/NCBI
29.	Nurse P: Ordering S phase and M phase in the cell cycle. Cell. 79:547–550. 1994. View Article : Google Scholar : PubMed/NCBI
30.	Morgan DO: Principles of CDK regulation. Nature. 374:131–134. 1995. View Article : Google Scholar : PubMed/NCBI
31.	Zafonte BT, Hulit J, Amanatullah DF, Albanese C, Wang C, Rosen E, Reutens A, Sparano JA, Lisanti MP and Pestell RG: Cell-cycle dysregulation in breast cancer: breast cancer therapies targeting the cell cycle. Front Biosci. 5:D938–D961. 2000. View Article : Google Scholar : PubMed/NCBI
32.	Kouraklis G, Theocharis S, Vamvakas P, Vagianos C, Glinavou A, Giaginis C and Sioka C: Cyclin D1 and Rb protein expression and their correlation with prognosis in patients with colon cancer. World J Surg Oncol. 4:52006. View Article : Google Scholar : PubMed/NCBI
33.	Domagala W, Welcker M, Chosia M, Karbowniczek M, Harezga B, Bartkova J, Bartek J and Osborn M: p21/WAF1/Cip1 expression in invasive ductal breast carcinoma: Relationship to p53, proliferation rate, and survival at 5 years. Virchows Arch. 439:132–140. 2001.PubMed/NCBI