- Aanvrager: Mevrouw H. Zuo
Pharmacology 2018 London UK 18 dec 2018 - 20 dec 2018
Inhibition of A-kinase anchoring proteins attenuated TGF-?1/cigarette smoke induced cell migration in human airway epithelial cells
Haoxiao Zuo| Dept. of Molecular Pharmacology and Groningen Research Institute for Asthma and COPD (GRIAC) - University of Groningen| 2018 BPS
Epithelial-to-mesenchymal transition (EMT) is a process characterized by the loss of epithelial phenotype and the acquisition of a mesenchymal phenotype. EMT plays a critical role in chronic obstructive pulmonary diseases (COPD), a pulmonary disease induced by air pollution and in particular by cigarette smoke (CS). The phosphodiesterase (PDE) 4 inhibitor rolipram has been shown to inhibit transforming growth factor beta 1 (TGF-?1) mediated EMT in A549 cells, indicating that the cyclic AMP (cAMP) pathway might be worthwhile to be targeted to attenuate EMT-associated lung diseases. A central feature of cAMP signaling is the compartmentalization via A-kinase anchoring proteins (AKAPs). The role of AKAPs and their therapeutic value in the process of EMT have barely studied yet. In my project, I am trying to investigate the potential therapeutic role of AKAPs in TGF-?1/ CS induced EMT. Thanks to the financial support from Longfonds, I was able to join the winter meeting of British Pharmacological Society 2018 which was held in London, UK, during December 18-20, 2018 and presented our recent findings in the ‘Molecular and Cellular Pharmacology’ session.
We demonstrated that TGF-?1 stimulation decreased Ezrin gene expression and increased AKAP95 and Yotiao gene expressions. St-Ht31, a inhibitory peptide to disrupt the interaction between AKAP and protein kinase A, led to a strong decrease of E-cadherin (mRNA and protein), but further augmented TGF-?1-induced E-cadherin (protein) decrease and counterbalanced TGF-?1-induced collagen 1?1 (protein) upregulation. Silencing of Ezrin, AKAP95, Yotiao primarily diminished collagen upregulation by TGF-?1, moreover, significantly slowing down the wound closure induced by TGF-?1. Additionally, CS exposure for 24 hours significantly increased phospho-SMAD2 protein expression and TGF-?1 release, also, augmented cell migration, indicating that CS could potentially induce EMT via TGF-?1. Some experts in this field showed their interests in our research and we talked with each other about the potential directions related to cAMP compartmentalization in the future.
In addition, I am interested in cAMP signaling pathway in other field since I believe that findings in other fields inspire me with new ideas in my own research lines. During the conference, I met with Dr. Bertollotto from Brazil. She mainly focused on the role of multi-drug resistance proteins, which acted as cellular export pump for cAMP and cGMP, in bladder, prostate and urethra. Also, it was demonstrated by Dr. Hoshi that PDE4 inhibitors synergistically interact with long-acting-?2-adrenoceptor agonist in bronchial epithelial cells. Personally, I am also interested in the cancer-related research and I found many studies focused on solid tumor. Indeed, these studies open my mind and give me some inspirations for future possibilities.
In conclusion, during BPS 2018, I talked to many experts about my own research and the future directions. With their professional advices about the experimental design, I believe that my study will be more comprehensive. Also, I expanded my networks with many scientists from other countries and I had more opportunities to know some other fields which I am interested in but not very familiar with. Thanks to Longfonds, I have this great opportunity to join the conference.