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

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.

Dietary Non-nutritive Factors in Targeting of Regulatory Molecules in Colorectal Cancer: An Update

“…Ursolic acid (UA), a natural pentacyclictriterpenoid carboxylic acid distributed in medical herbs, exerts antitumor effects by modulating COX-2 in colon cancer cells (Wang et al, 2013). The combination of hexahydrocurcumin and 5-fluorouracil modulates ACF formation and the expression of COX-2 on dimethylhydrazine-induced colon cancer in rats (Srimuangwong et al, 2012).…”

Ursolic acid protects against ulcerative colitis via anti-inflammatory and antioxidant effects in mice

“…UA is well known to possess various biological activities, including anti-inflammatory (5,6), anticancer (7,8), hypoglycemic (9), antioxidant (10)(11)(12) and immunomodulatory activities (13). Previously, UA was reported to be involved in colitis in a number of publications (4,14,15).…”

Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation

“…UA is pentacyclic triterpenoid that is ubiquitously expressed in most plant species [8] . UA has been shown to exert anti-cancer [9] , anti-oxidative [10] , and anti-inflammatory [11] effects, in addition to conferring benefits in cognitive function [12] , asthma [13] , and colon cancer [14,15] . Of note, Pathak et al reported that UA inhibited activation of the STAT3 pathway, leading to the suppression of proliferation in human multiple myeloma cells [16] .…”