Akt/PKB signaling regulates cigarette smoke-induced pulmonary epithelial-mesenchymal transition.

Cigarette smoke (CS) is a major risk factor for the development of lung cancer and chronic obstructive pulmonary disease (COPD). Epithelial-mesenchymal transition (EMT) is found in invasive or metastatic phenotypes in lung cancer and COPD. MK-2206, a pan Akt inhibitor, has failed in clinical trials for solid tumors when administered alone at tolerated doses, but it has been shown to have synergistic effects when applied with certain molecular targeted agents. In this study, we investigated the working mechanism of MK-2206 in CS-induced pulmonary EMT both in vivo and in vitro. The expression of Akt, epithelial-mesenchymal transition (EMT) markers and signaling proteins were analyzed by immunohistochemistry, real-time PCR and Western blot in cigarette smoke extract (CSE)-treated pulmonary epithelia and CS-treated lung tissues in mice. We demonstrated that exposure of the epithelium to CSE and exposure of the mice to CS can induce EMT by activating the Akt signaling pathway. Intragastric application of MK-2206 at a low dose (50 mg/kg) reversed the changes of the key indicators of EMT in the lungs of CS-exposed mice, including TGF-β1, α-SMA, vimentin, MMP-9, MMP-2, S100A4, collagen deposition, and E-cadherin. MK-2206 at a non-cytotoxic concentration (0.5 μM) or Akt knockdown consistently reversed the changes of the key indicators of EMT in the pulmonary epithelia. Moreover, we found that the effects of Akt inhibition or knockdown on the CS/CSE-induced EMT acted via the TGF-β1/Akt/Smad/mTOR and Akt/P38 MAPK pathways. Taken together, our data offer a novel perspective on the molecular mechanism of Akt for CS-induced EMT. This finding may enhance the understanding of the mechanism behind the synergistic use of a low dose of MK-2206 to achieve antitumor efficacy with reduced adverse reactions in patients with lung cancer and COPD.

Jiang B ，Guan Y ，Shen HJ ，Zhang LH ，Jiang JX ，Dong XW ，Shen HH ，Xie QM ... -  《-》

Cigarette smoke-induced alveolar epithelial-mesenchymal transition is mediated by Rac1 activation.

Epithelial-mesenchymal transition (EMT) is the major pathophysiological process in lung fibrosis observed in chronic obstructive pulmonary disease (COPD) and lung cancer. Smoking is a risk factor for developing EMT, yet the mechanism remains largely unknown. In this study, we investigated the role of Rac1 in cigarette smoke (CS) induced EMT. EMT was induced in mice and pulmonary epithelial cells by exposure of CS and cigarette smoke extract (CSE) respectively. Treatment of pulmonary epithelial cells with CSE elevated Rac1 expression associated with increased TGF-β1 release. Blocking TGF-β pathway restrained CSE-induced changes in EMT-related markers. Pharmacological inhibition or knockdown of Rac1 decreased the CSE exposure induced TGF-β1 release and ameliorated CSE-induced EMT. In CS-exposed mice, pharmacological inhibition of Rac1 reduced TGF-β1 release and prevented aberrations in expression of EMT markers, suggesting that Rac1 is a critical signaling molecule for induction of CS-stimulated EMT. Furthermore, Rac1 inhibition or knockdown abrogated CSE-induced Smad2 and Akt (PKB, protein kinase B) activation in pulmonary epithelial cells. Inhibition of Smad2, PI3K (phosphatidylinositol 3-kinase) or Akt suppressed CSE-induced changes in epithelial and mesenchymal marker expression. Altogether, these data suggest that CS initiates EMT through Rac1/Smad2 and Rac1/PI3K/Akt signaling pathway. Our data provide new insights into the fundamental basis of EMT and suggest a possible new course of therapy for COPD and lung cancer.

Shen HJ ，Sun YH ，Zhang SJ ，Jiang JX ，Dong XW ，Jia YL ，Shen J ，Guan Y ，Zhang LH ，Li FF ，Lin XX ，Wu XM ，Xie QM ，Yan XF ... -  《-》

FERMT3 mediates cigarette smoke-induced epithelial-mesenchymal transition through Wnt/β-catenin signaling.

Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Epithelial-mesenchymal transition (EMT) is an essential pathophysiological process in COPD and plays an important role in airway remodeling, fibrosis, and malignant transformation of COPD. Previous studies have indicated FERMT3 is downregulated and plays a tumor-suppressive role in lung cancer. However, the role of FERMT3 in COPD, including EMT, has not yet been investigated. The present study aimed to explore the potential role of FERMT3 in COPD and its underlying molecular mechanisms. Three GEO datasets were utilized to analyse FERMT3 gene expression profiles in COPD. We then established EMT animal models and cell models through cigarette smoke (CS) or cigarette smoke extract (CSE) exposure to detect the expression of FERMT3 and EMT markers. RT-PCR, western blot, immunohistochemical, cell migration, and cell cycle were employed to investigate the potential regulatory effect of FERMT3 in CSE-induced EMT. Based on Gene Expression Omnibus (GEO) data set analysis, FERMT3 expression in bronchoalveolar lavage fluid was lower in COPD smokers than in non-smokers or smokers. Moreover, FERMT3 expression was significantly down-regulated in lung tissues of COPD GOLD 4 patients compared with the control group. Cigarette smoke exposure reduced the FERMT3 expression and induces EMT both in vivo and in vitro. The results showed that overexpression of FERMT3 could inhibit EMT induced by CSE in A549 cells. Furthermore, the CSE-induced cell migration and cell cycle progression were reversed by FERMT3 overexpression. Mechanistically, our study showed that overexpression of FERMT3 inhibited CSE-induced EMT through the Wnt/β-catenin signaling. In summary, these data suggest FERMT3 regulates cigarette smoke-induced epithelial-mesenchymal transition through Wnt/β-catenin signaling. These findings indicated that FERMT3 was correlated with the development of COPD and may serve as a potential target for both COPD and lung cancer.

Su X ，Chen J ，Lin X ，Chen X ，Zhu Z ，Wu W ，Lin H ，Wang J ，Ye X ，Zeng Y ... -  《RESPIRATORY RESEARCH》

Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production.

Liu YN ，Guan Y ，Shen J ，Jia YL ，Zhou JC ，Sun Y ，Jiang JX ，Shen HJ ，Shu Q ，Xie QM ，Xie Y ... -  《RESPIRATORY RESEARCH》

Ginsenoside Rg1 Attenuates Cigarette Smoke-Induced Pulmonary Epithelial-Mesenchymal Transition via Inhibition of the TGF-β1/Smad Pathway.

Guan S ，Xu W ，Han F ，Gu W ，Song L ，Ye W ，Liu Q ，Guo X ... -  《-》