Flavonoids from Orostachys japonicus A. Berger Inhibit the Invasion of LnCaP Prostate Carcinoma Cells by Inactivating Akt and Modulating Tight Junctions

Abstract

Tight junctions (TJs) are a mode of cell-to-cell adhesion in epithelial or endothelial cells, and serve as a physical barrier to maintenance of homeostasis in body by controlling paracellular transport. Claudins are the most important molecules of the TJs, but paradoxically these proteins are frequently over-expressed in cancers and their overexpression is implicated in the invasive potential of cancer. Hence, we investigated the effects of flavonoids extracted from Orostachys japonicus A. Berger (FEOJ) on TJs and the expression of claudins as well as cancer invasion along with in LnCaP human prostate cancer. FEOJ suppressed cancer cell motility and invasiveness at the concentrations where FEOJ did not show anti-proliferative activity. FEOJ increased transepithelial electrical resistance (TER) associated with tightening TJs, and suppressed expression of claudin proteins. Furthermore, FEOJ suppressed the activities of MMP-2 and -9 in a dose-dependent manner, which came from the activation of tissue inhibitor of metalloproteinases (TIMPs) by FEOJ. FEOJ suppressed migration and invasion by suppressing PI3K/Akt signaling pathway. Taken together, this study suggest that FEOJ suppresses cancer migration and invasion by tightening TJs through the suppression of claudin expression, and by suppressing MMPs in LnCaP human prostate cancer cells, which at least in part results from the suppression of PI3K/Akt signaling pathway.

Epithelial‐mesenchymal transition during invasion of cutaneous squamous cell carcinoma is paralleled by AKT activation

“…In vivo skin penetration studies with human volunteers showed that flavonoids were not only absorbed at the skin surface, but also penetrated into deeper skin layers . Flavonoids have been shown to inhibit invasion and migration of prostate carcinoma and glioblastoma cells, respectively by suppressing the AKT pathway . In a previous study we demonstrated that the flavonoid luteolin is able to suppress AKT‐signalling in both the primary MET1 and metastatic MET4 cSCC cells and could therefore be used as a therapy to inhibit AKT .…”

HGF and the regulation of tight junctions in human prostate cancer cells

“…Claudin proteins have been targeted as a means of modulating TJ function. Tight junctions in human prostate cells can be modulated successfully, as shown by a study suggesting that flavonoids extracted from Orostachys japonicus A. Berger suppressed cancer migration and invasion by tightening TJs through the suppression of claudin expression, and by suppressing MMPs in LNCaP human prostate cancer cells, which at least in part resulted from the suppression of the PI3K/Akt signaling pathway (44).…”

Aqueous extract of Orostachys japonicus A. Berger exerts immunostimulatory activity in RAW 264.7 macrophages

“…Orostachys japonicus A. Berger (Crassulaceae) (OJ), also known as Wa-song in Korea, is used as a folk medication; its main habitat is on the surface of mountain rocks in Korea and Japan. OJ is a medicinal plant with immunoregulatory, anti-febrile, antidote, and anticancer activities (Jin Kwon and Kwangsoo Han, 2004;Kim et al, 2011;Lee et al, 2011;Ryu et al, 2014;Ryu et al, 2012;Shin et al, 2013;Yoon et al, 2000). It is reported that OJ increased CD4-and CD8-T cells and the production of interferon γ in BALB/c mice (Jin Kwon and Kwangsoo Han, 2004).…”