Resolvin D1 inhibits TGF-β1-induced epithelial mesenchymal transition of A549 lung cancer cells via lipoxin A4 receptor/formyl peptide receptor 2 and GPR32.

Epithelial-mesenchymal-transition (EMT) is a key event for tumor cells to initiate metastasis which lead to switching of E-cadherin to N-cadherin. Resolvins are known to promote the resolution of inflammation and phagocytosis of macrophages. However, the role of resolvins in EMT of cancer is not known. Therefore, we examined the effects of resolvins on transforming growth factor, beta 1 (TGF-β1)-induced EMT. Expression of E-cadherin and N-cadherin in A549 lung cancer cells was evaluated by Western blot and confocal microscopy. Involvement of lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) was examined by gene silencing. TGF-β1 induced expression of N-cadherin in A549 lung cancer cells, and resolvin D1 and D2 inhibited the expression of N-cadherin at low concentrations (1-100 nM). Resolvin D1 and D2 also suppressed the expression of zinc finger E-box binding homeobox 1 (ZEB1). The effects of resolvin D1 and D2 were confirmed in other lung cancer cell lines such as H838, H1299, and H1703. Resolvin D1 and D2 did not affect the proliferation of A549 lung cancer cells. Resolvin D1 and D2 also suppressed the TGF-β1-induced morphological change. Resolvin D1 and D2 also inhibited the TGF-β1-induced migration and invasion of A549 cells. Resolvin D1 is known to act via ALX/FPR2 and GPR32. Thus, we examined the involvement of ALX/FPR2 and GPR32 in the suppressive effects of resolvin D1 on TGF-β1-induced EMT of A549 cells. Gene silencing of ALX/FPR2 and GPR32 blocked the action of resolvin D1. Overexpression of ALX/FPR2 or GPR32 increased the effects of resolvin D1. These results suggest that resolvin D1 inhibited TGF-β1-induced EMT via ALX/FPR2 and GPR32 by reducing the expression of ZEB1.

Lee HJ ，Park MK ，Lee EJ ，Lee CH ... -  《-》

Transglutaminase-2 induces N-cadherin expression in TGF-β1-induced epithelial mesenchymal transition via c-Jun-N-terminal kinase activation by protein phosphatase 2A down-regulation.

Epithelial-mesenchymal-transition (EMT) is a key event for tumour cells to initiate metastasis leading to switching of E-cadherin to N-cadherin. Transglutaminase-2 (Tgase-2) expression is increased in TGF-β1-induced EMT in A549 lung cancer cells or other lung cancer cells. The role and underlying mechanism of Tgase-2 in N-cadherin switching of TGF-β1-induced EMT are not known. The involvement and mechanisms of Tgase-2 were investigated in A549 cells using chemical inhibitors, gene silencing and over-expression. TGF-β1-induced EMT was suppressed by cystamine or gene silencing of Tgase-2. Suppression of Tgase-2 or the c-Jun-N-terminal kinase (JNK) inhibitor, SP600125, significantly reduced and over-expression of Tgase-2 increased the expression of N-cadherin. The relationship between Tgase-2 and JNK in the TGF-β1-induced EMT of A549 cells was examined using Tgase-2 over-expressed A549 cells (A549(TG2)) and Tgase-2 silenced A549 cells (A549(shTG2)). JNK activation was significantly increased in A549(TG2) cells and decreased in A549(shTG2) cells. In contrast, PP2A expression was decreased in A549(TG2) and A549 cells and increased in A549(shTG2) cells. The involvement of Tgase-2 in N-cadherin expression was also confirmed in an in vivo lung cancer orthotopic model by injection of A549(WT) and A549(shTG2) cells into SCID mice. Tgase-2 expressing A549(WT) cells-injected mice group showed increased expressions of N-cadherin and JNK activation, but decreased expression of PP2A in lung cancer tissue comparing with the A549(shTG2) cells-injected group. These results suggested that Tgase-2 induces N-cadherin expression of TGF-β1-induced EMT via JNK activation by PP2A down-regulation, and Tgase-2/PP2A/JNK might be a novel axis that affects N-cadherin switching in the EMT of A549 lung cancer cells.

Park MK ，You HJ ，Lee HJ ，Kang JH ，Oh SH ，Kim SY ，Lee CH ... -  《-》

Aspirin-triggered resolvin D1 inhibits TGF-β1-induced EMT through the inhibition of the mTOR pathway by reducing the expression of PKM2 and is closely linked to oxidative stress.

Liu Y ，Yuan X ，Li W ，Cao Q ，Shu Y ... -  《-》

Resveratrol inhibits TGF-β1-induced epithelial-to-mesenchymal transition and suppresses lung cancer invasion and metastasis.

Epithelial-to-mesenchymal transition (EMT) is a cellular process during which epithelial polarized cells become motile mesenchymal-appearing cells, which in turn promotes carcinoma invasion and metastasis. Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural polyphenolic compound found in grapes, red wine and several other plants. Numerous reports in the literature indicate that resveratrol can suppress cancer invasion and metastasis. However, the underlying mechanisms of inhibiting metastasis by resveratrol are complex, not fully elucidated and the subject of intense scientific debate. Despite evidence indicating that EMT can be a target for resveratrol, little is known about the effect of resveratrol on lung cancer cells. Our previous studies demonstrated that TGF-β1 induces EMT to promote lung adenocarcinoma invasion and metastasis. To understand the repressive role of resveratrol in lung cancer invasion and metastasis, we sought to investigate the potential use of resveratrol as an inhibitor of TGF-β1-induced EMT development in A549 lung cancer cells in vitro. Here we show that when A549 cells are treated with TGF-β1 and resveratrol, the latter inhibits the initiation of TGF-β1-induced EMT. Our results show that 20 μM resveratrol increases expression of the epithelial phenotype marker E-cadherin and represses the expression of the mesenchymal phenotype markers, Fibronectin and Vimentin during the initiation of TGF-β1-induced EMT. Resveratrol also inhibits expression of EMT-inducing transcription factors Snail1 and Slug, although the expression of the Twist1 transcription factor remained unchanged. Resveratrol inhibits the TGF-β1-induced increase in cell adhesion, migration and invasion of A549 lung cancer cells. Taken together, our findings provide new evidence that resveratrol suppresses lung cancer invasion and metastasis in vitro through inhibiting TGF-β1-induced EMT.

Wang H ，Zhang H ，Tang L ，Chen H ，Wu C ，Zhao M ，Yang Y ，Chen X ，Liu G ... -  《-》

Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-β1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance.

The epithelial-mesenchymal transition (EMT) is a pivotal cellular process during which epithelial polarized cells become motile mesenchymal-appearing cells, which, in turn, promotes the metastatic potential of cancer. Ginseng is a perennial plant belonging to the genus Panax that exhibits a wide range of pharmacological and physiological activities. Ginsenosides 20-Rg3, which is the active component of ginseng, has various medical effects, such as anti-tumorigenic, anti-angiogenesis, and anti-fatiguing activities. In addition, ginsenosides 20(S)-Rg3 and 20(R)-Rg3 are epimers, and this epimerization is produced by steaming. However, the possible role of 20(S)-Rg3 and 20(R)-Rg3 in the EMT is unclear. We investigated the effect of 20(S)-Rg3 and 20(R)-Rg3 on the EMT. Transforming growth factor-beta 1 (TGF-β1) induces the EMT to promote lung adenocarcinoma migration, invasion, and anoikis resistance. To understand the repressive role of 20(S)-Rg3 and 20(R)-Rg3 in lung cancer migration, invasion, and anoikis resistance, we investigated the potential use of 20(S)-Rg3 and 20(R)-Rg3 as inhibitors of TGF-β1-induced EMT development in A549 lung cancer cells in vitro. Here, we show that 20(R)-Rg3, but not 20(S)-Rg3, markedly increased expression of the epithelial marker E-cadherin and repressed Snail upregulation and expression of the mesenchymal marker vimentin during initiation of the TGF-β1-induced EMT. 20(R)-Rg3 also inhibited the TGF-β1-induced increase in cell migration, invasion, and anoikis resistance of A549 lung cancer cells. Additionally, 20(R)-Rg3 markedly inhibited TGF-β1-regulated matrix metalloproteinase-2 and activation of Smad2 and p38 mitogen activated protein kinase. Taken together, our findings provide new evidence that 20(R)-Rg3 suppresses lung cancer migration, invasion, and anoikis resistance in vitro by inhibiting the TGF-β1-induced EMT.

Kim YJ ，Choi WI ，Jeon BN ，Choi KC ，Kim K ，Kim TJ ，Ham J ，Jang HJ ，Kang KS ，Ko H ... -  《-》