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,Yu; Yuan,Xiaolong; Li,Wenhui; Cao,Qianqian; Shu,Yusheng

doi:10.3892/ijmm.2016.2721

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

Authors:
- Yu Liu
- Xiaolong Yuan
- Wenhui Li
- Qianqian Cao
- Yusheng Shu
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Affiliations: Department of Cardiothoracic Surgery, Clinical Medicine College of Yangzhou University, Subei People's Hospital, Yangzhou, Jiangsu 225001, P.R. China
Published online on: August 29, 2016 https://doi.org/10.3892/ijmm.2016.2721
Pages: 1235-1242

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Abstract

Transforming growth factor-β1 (TGF-β1) is a potent stimulator of the epithelial-to-mesenchymal transition (EMT), which is a key event in the initiation of tumor cell metastasis. Aspirin-triggered resolvin D1 (AT-RvD1) is known to be involved in the resolution of inflammation; however, whether AT-RvD1 exerts effects on TGF-β1-induced EMT remains unclear. Thus, we first explored the effects of AT-RvD1 on the EMT of lung cancer cells. Treatment with TGF-β1 increased the level of reactive oxygen species (ROS) and reduced the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The expression of E-cadherin in A549 lung cancer cells was reduced, and the expression of vimentin was enhanced. AT-RvD1 enhanced the expression of E-cadherin in a concentration‑dependent manner and suppressed the expression of Nrf2 and vimentin. AT-RvD1 did not affect the proliferation of A549 lung cancer cells whereas it suppressed the TGF-β1‑induced migration and invasion of A549 cells. The expression of pyruvate kinase M2 (Pkm2), which is associated with TGF-β-induced factor homeobox 2 (TGIF2), was significantly increased during the TGF-β1-induced EMT of A549 lung cancer cells. The mTOR pathway is known to regulate the expression of various glycolytic enzymes including Pkm2. We examined the involvement of the mTOR pathway in the suppressive effects of AT-RvD1 on Pkm2 expression in A549 cells. The mTOR activator restored the expression of Pkm2 and partially downregulated the expression of E-cadherin. However, the mTOR activator had no clear effect on the TGF-β1-induced EMT. These results suggest that AT-RvD1 is closely linked to oxidative stress and partially inhibits TGF-β1-induced EMT through the inhibition of the mTOR pathway by reducing the expression of Pkm2.

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