Ursolic Acid Simultaneously Targets Multiple Signaling Pathways to Suppress Proliferation and Induce Apoptosis in Colon Cancer Cells

Jingshu Wang,Dingbo Shi,Lingyi Fu,Wuguo Deng,Jianding Cheng,Yun Tian,Xiaohong Zhang,Wenlin Huang,Wangbing Chen,Wei Guo,Liqun Liu,Huijuan Qiu,Chunhong Yan

doi:10.1371/journal.pone.0063872

Abstract

Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid distributed in medical herbs, exerts antitumor effects and is emerging as a promising compound for cancer prevention and therapy, but its excise mechanisms of action in colon cancer cells remains largely unknown. Here, we identified the molecular mechanisms by which UA inhibited cell proliferation and induced apoptosis in human colon cancer SW480 and LoVo cells. Treatment with UA led to significant inhibitions in cell viability and clone formation and changes in cell morphology and spreading. UA also suppressed colon cancer cell migration by inhibiting MMP9 and upregulating CDH1 expression. Further studies showed that UA inhibited the phosphorylation of Akt and ERK proteins. Pretreatment with an Akt or ERK-specific inhibitor considerably abrogated the proliferation inhibition by UA. UA also significantly inhibited colon cancer cell COX-2 expression and PGE2 production. Pretreatment with a COX-2 inhibitor (celecoxib) abrogated the UA-induced cell proliferation. Moreover, we found that UA effectively promoted NF-κB and p300 translocation from cell nuclei to cytoplasm, and attenuated the p300-mediated acetylation of NF-κB and CREB2. Pretreatment with a p300 inhibitor (roscovitine) abrogated the UA-induced cell proliferation, which is reversed by p300 overexpression. Furthermore, UA treatment induced colon cancer cell apoptosis, increased the cleavage of PARP, caspase-3 and 9, and trigged the release of cytochrome c from mitochondrial inter-membrane space into cytosol. These results indicate that UA inhibits cell proliferation and induces apoptosis in colon cancer cells through simultaneous modulation of the multiple signaling pathways such as MMP9/CDH1, Akt/ERK, COX-2/PGE2, p300/NF-κB/CREB2, and cytochrome c/caspase pathways.

Highlights

Colon and rectal cancer, the third most common cancer worldwide, has become one of the leading causes of death from cancers [1]
The results showed the anti-proliferation, anti-migration and proapoptotic effects of Ursolic acid (UA) in colon cancer cells were mediated through simultaneous modulation of multiple signaling pathways, including MMP9/CDH1, Akt/ERK, COX-2/prostaglandin E2 (PGE2), p300/NFkB/CREB2 and cytochrome c/caspase-dependent pathways
The results showed that knockdown of p300 expression by si-p300 markedly enhanced the apoptosis induction mediated by UA (Fig. 7E), confirming the role of p300 signaling in regulating UA-induced apoptosis in colon cancer cells

Summary

Introduction

Colon and rectal cancer (colorectal cancer, CRC), the third most common cancer worldwide, has become one of the leading causes of death from cancers [1]. Chemotherapy and radiotherapy are the primary and common treatments for colorectal cancer. Chemotherapy is adjuvant to surgery, the cure rate of colorectal cancer was still not ideal, especially for the later stage patients. The metastasis and recurrence after surgery or the produced chemotherapy resistance usually leads to the final death. Complementary and alternative treatment strategy has become necessary to improve the survival rate of colon cancer patients. Chinese herbal medicine is becoming more and more popular in cancer treatments combined with conventional therapy due to its natural origin, low toxicity and effectiveness to prevent and treat cancers, including colon cancer [2]

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Conclusion