Isoalvaxanthone inhibits colon cancer cell proliferation, migration and invasion through inactivating Rac1 and AP‐1

Abstract

Isoalvaxanthone (IAX) is a bioactive xanthone isolated from Cudrania cochinchinensis (Lour.). However, the function and mechanism of this compound in cancer migration and invasion have not been elucidated to date. In this study, we found that IAX could suppress various steps of tumor metastasis including proliferation, migration and invasion in a dose-dependent manner on colorectal cancer cells. Especially matrix metalloproteinase 2 (MMP-2), the pivotal factor in cancer invasion, was suppressed both on activation and expression after treated with IAX. To understand the underlying mechanism of IAX on the inhibitory effect of proliferation, migration and invasion, we demonstrated that IAX could significantly inhibit the activation of Rac1 but has undetectable effect on GTP-RhoA, GTP-Cdc42 and the phosphorylation of ERK1/2, p38 MAPK and JNK. Moreover, IAX showed little influence on the transcriptional activity of nuclear transcription factor jB (NF-jB) but strongly inhibited that of activator protein-1 (AP-1), which is the downstream transcriptional factor of Rac1. Together, our results indicate that IAX exerts anticancer effect in SW620 cells by targeting MMP-2 via regulating the activity of Rac1 and AP-1. These results are the first to reveal the function of IAX in tumor metastasis and its underlying molecular mechanism, thus suggest IAX to be a promising antimetastatic agent.Colorectal carcinoma is the third most common form of cancer and the second leading cause of morbidity and mortality in the world.1 Metastasis, a main cause of death in cancer patients, contributes to the high mortality of colorectal cancer, despite most early stage colorectal cancer is curable with surgical resection. In metastasis, malignant tumor cells moved from the primary tumor to a secondary distant organ through a complex multistage process involving the coordination of several signaling pathways that allow changes in cell morphology, migration and invasion.2,3 During the process of metastasis, degradation of the extracellular matrix (ECM) by proteases such as matrix metalloproteinases (MMPs) is important. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are the most vital proteases for the degradation of the main constituent of the basement membrane, type IV collagen and are, therefore, pivotal for cancer invasion and metastasis. 4 The Rho family proteins (RhoA, Rac1 and Cdc42) are small GTP-binding proteins with a distinct function in cell survival, cytoskeleton organization, adhesion and motility, thus become important targets of cancer chemotherapy. 5,6 It is now known that these biological activities are coordinated by the concerted action of different Rho/Rac subfamily members. For instance, RhoA function is required for the initial formation of the lamellipodia and the establishment of focal adhesions and stress fibers, Rac1 promotes membrane ruffles and lamellipodia and Cdc42 trigger filopodia in the leading edge of migrating cells.7 Small GTPases are also molecular switches that trigger signaling cascades in response to upstrea...

Anti-metastatic Effects on B16F10 Melanoma Cells of Extracts and Two Prenylated Xanthones Isolated from Maclura amboinensis Bl. Roots

“…roots remarkably suppressed the multistep of metastatic process of B16F10 cells proliferation, adhesion, invasion and migration at the non-toxic effective doses, indicating that the presence of these active xanthones may be in part responsible for their effects on cell proliferation and metastasis capability of this metastatic cells. Our observations correlate with the earlier reports that two main xanthones of isoalvaxanthone isolated from Cudrania cochinchinensis (Lour) and cudratricusxanthone G, isolated from Cudrania tricuspidata exerted anti-metastatic action in human colorectal carcinoma (SW620) cells by targeting MMP-2 through regulating the activities of Rac 1, Cdc 42, and their downstream transcriptional factor AP-1 (Wang et al, 2010;Kuang et al, 2011). Further studies have to find out the exact molecular mechanism of actions of the active xanthones and other isolated compounds in inhibiting the cascade of events of metastasis.…”

“…were found to possess antiinflammatory (Chang et al, 2008), anti-lipid peroxidative (Chang et al, 1994), antioxidative Lee et al, 2006;Jeong et al, 2009Jeong et al, : 2012, hepatoprotective , antibacterial (Fukai et al, 2004), antifungal , antitumor effects and cytotoxicity against various cancer cells (Seo, et al, 2001;Zou et al, 2004;Wang et al, 2005Wang et al, : 2010Kuang et al, 2011). More extensive phytochemical and pharmacological studies, several xanthones and flavonoids as the main active components have been identified from this genus and some of them have been reported to possess significant pharmacological properties, including anti-inflammatory (Lin et al, 2012), anti-cancer Wang et al, 2010;Kuang et al, 2011), antibacterial (Fukai, et al, 2004) and anti-HIV (Groweiss et al, 2000) activities. For instance, macluraxanthone B and C isolated from Maclura tinctoria exhibited anti-HIV activity (Groweiss et al, 2000).…”

Designer Xanthone: An Inhibitor Scaffold for MDR-Involved Human Glutathione Transferase Isoenzyme A1-1

“…It appears that either hydrophobic or H-bonding interactions would lead to a tighter contact with the enzyme binding site, features that, when combined, would lead to a further substantial increase of the binding potency. Comparing 14 and 15 with 16 strongly suggests the prevalence of 1,5-di-substitution (16), at the peri-positions, over their mono-substituted variants (14,15). This is supported by the clustering caused during docking where the iodine in 14 and 15 is placed in a very hydrophobic region, whereas in analogue 16, steric constraint forces iodine atoms into less hydrophobic positions.…”

Diet, nutrients, phytochemicals, and cancer metastasis suppressor genes

“…Glutamate supplementation [22], red grape skin polyphenolic extract [23], acacetin (a flavone found in honey and other sources) [24], isoalvaxanthone (a polyphenolic xanthone, which is biosynthetically related to flavonoids found in Cudrania cochinchinensis, Lour. and used in Chinese fold medicine) [25], and genistein (an isoflavone found in soy products) [26] inhibit p38 and/or its phosphorylation. Natural compounds that increase p38 and/or p38 phosphorylation in various cancer cell types include the following: glutamine, tyrosine and phenylalanine, and methionine restriction [27], lupulone (a prenylated flavonoid found in hops used in the manufacture of beer) [28], celastrol (a quinone methide triterpene extracted from the root bark of Tripterygium wilfordii, which in Chinese medicine is known as Thunder of God Vine) [29], berberine (an isoquinoline alkaloid with medicinal properties widely distributed in plants, notably Oregon grape, Mahonia aquifolium) [30], quercetin (a flavonol found in fruits, vegetables, leaves and grains) [31], and β-caryophyllene (a bicyclic sessquiterpene found in many essential oils, rosemary, hops, and black pepper) [32].…”