Role of adenosine monophosphate-activated protein kinase on cell migration, matrix contraction, and matrix metalloproteinase-1 and matrix metalloproteinase-2 production in nasal polyp-derived fibroblasts

Ji Young Um; Seoung Ae Lee; Joo Hoo Park; Jae Min Shin; Il Ho Park; Heung Man Lee

doi:10.2500/ajra.2017.31.4477

Role of adenosine monophosphate-activated protein kinase on cell migration, matrix contraction, and matrix metalloproteinase-1 and matrix metalloproteinase-2 production in nasal polyp-derived fibroblasts

Ji Young Um, Seoung Ae Lee, Joo Hoo Park, Jae Min Shin, Il Ho Park, Heung Man Lee

Department of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

Purpose: Activation of adenosine monophosphate-activated protein kinase (AMPK) by metformin, as a master regulator of metabolism, is involved in airway tissue remodeling. Here, we investigated the physical role of AMPK on cell migration, matrix contraction, and the production of matrix metalloproteinases (MMP) in nasal polyp- derived fibroblasts (NPDF). Methods: Primary NPDFs from six patients with chronic rhinosinusitis and nasal polyps were isolated and cultured. To assess the effect of AMPK on fibroblast migration, we conducted scratch and migration assays in NPDF treated with metformin and/or compound C. A collagen gel contraction assay measured activity of contractile. MMP expression was measured with reverse transcription-polymerase chain reaction, Western blot, and zymography. To evaluate for specific AMPK action, we examined by AMPK small interfering RNA. Results: Metformin, an activator of AMPK, significantly inhibited cell migration in NPDFs in a dose-dependent manner. Compound C, an inhibitor of AMPK, partially reversed the inhibitory effect of metformin. Metformin also significantly decreased contractile activity, with a concomitant reduction in the production of MMP-1 and MMP-2 but not of MMP-9. Specific silencing that targeted AMPK resulted in the enhancement of mobility and contractility and in the production of MMP-1 and MMP-2. Conclusion: AMPK played an important role in regulating cell migration, matrix contraction, and MMP production in NPDFs, which provided data that AMPK activator might be a therapeutic target for the prevention of tissue remodeling in nasal polyps.

Original language	English
Pages (from-to)	357-363
Number of pages	7
Journal	American Journal of Rhinology and Allergy
Volume	31
Issue number	6
DOIs	https://doi.org/10.2500/ajra.2017.31.4477
Publication status	Published - 2017 Nov 1

Bibliographical note

Funding Information:
This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI15C1512) and by the Basic Science Research Program through the National Research Foundation of Korea, which is funded by the Ministry of Education (2013R1A1A2059716)

Funding Information:
1 Reagents Seoul,Korea,2InstituteforIVDSupportcenterKoreaUniversityGuroHospital,KoreaFromtheDepartmentofBiomedicalScience,KoreaUniversity,CollegeofMedicine, Metformin and compound C were purchased from Sigma-Aldrich University,DCollege ofOMedicine, Seoul, Korea,N3Research-DrivenOHospital,TKorea Uni- CCo. (St. LOouis, MO).PTranswellsYl (Millipore Corp, Bedford, MA) were versityGuroHospital,KoreaUniversity,CollegeofMedicine,Seoul,SouthKorea,and purchased from Corning Life Sciences (Tewksbury, MA). 4Department of Otorhinolaryngology—Head and Neck Surgery, Korea University, J.Y.UmandS.A.LeecontributedequallytothisworkCollegeofMedicine,Seoul,Korea NPDF Culture ThisstudywassupportedbyagrantfromtheKoreanHealthTechnologyR&DProject, Six nasal polyp tissues (from three male and three female subjects) Ministry of Health & Welfare, Republic of Korea (HI15C1512) and by the Basic Science were collected from patients with chronic rhinosinusitis and nasal Research Program through the National Research Foundation of Korea, which is funded polyps who underwent endoscopic surgery in the Department of by the Ministry of Education (2013R1A1A2059716) Otorhinolaryngology. Some patients were excluded due to use of Theauthorshavenoconflictsofinteresttodeclarepertainingtothisarticle systemic steroids, immune modulatory drugs, or antibiotics within 4 AddresscorrespondencetoHeung-ManLee,M.D,DepartmentofOtorhinolaryngo- weeks before surgery, and a history of smoking. None of the patients logy—HeadandNeckSurgery,GuroHospital,KoreaUniversityCollegeofMedicine, had common allergies, asthma, or aspirin sensitivity. This study was E-mailaddress:lhman@korea.ac.kr148Guro-dongro,Guro-gu,Seoul08308,SouthKorea approved by the ethics committee of the Korea University Institu-Copyright© 2017,OceanSidePublications,Inc.,U.S.A. tional Review Board at Korea University Medical Center with the principles of the Declaration of Helsinki (KUGGR-2010–015). Written

Publisher Copyright:
© 2017, OceanSide Publications, Inc., U.S.A.

ASJC Scopus subject areas

Immunology and Allergy
Otorhinolaryngology

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10.2500/ajra.2017.31.4477

Cite this

Um, J. Y., Lee, S. A., Park, J. H., Shin, J. M., Park, I. H., & Lee, H. M. (2017). Role of adenosine monophosphate-activated protein kinase on cell migration, matrix contraction, and matrix metalloproteinase-1 and matrix metalloproteinase-2 production in nasal polyp-derived fibroblasts. American Journal of Rhinology and Allergy, 31(6), 357-363. https://doi.org/10.2500/ajra.2017.31.4477

Role of adenosine monophosphate-activated protein kinase on cell migration, matrix contraction, and matrix metalloproteinase-1 and matrix metalloproteinase-2 production in nasal polyp-derived fibroblasts. / Um, Ji Young; Lee, Seoung Ae; Park, Joo Hoo et al.
In: American Journal of Rhinology and Allergy, Vol. 31, No. 6, 01.11.2017, p. 357-363.

Research output: Contribution to journal › Article › peer-review

Um, JY, Lee, SA, Park, JH, Shin, JM, Park, IH & Lee, HM 2017, 'Role of adenosine monophosphate-activated protein kinase on cell migration, matrix contraction, and matrix metalloproteinase-1 and matrix metalloproteinase-2 production in nasal polyp-derived fibroblasts', American Journal of Rhinology and Allergy, vol. 31, no. 6, pp. 357-363. https://doi.org/10.2500/ajra.2017.31.4477

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title = "Role of adenosine monophosphate-activated protein kinase on cell migration, matrix contraction, and matrix metalloproteinase-1 and matrix metalloproteinase-2 production in nasal polyp-derived fibroblasts",

abstract = "Purpose: Activation of adenosine monophosphate-activated protein kinase (AMPK) by metformin, as a master regulator of metabolism, is involved in airway tissue remodeling. Here, we investigated the physical role of AMPK on cell migration, matrix contraction, and the production of matrix metalloproteinases (MMP) in nasal polyp- derived fibroblasts (NPDF). Methods: Primary NPDFs from six patients with chronic rhinosinusitis and nasal polyps were isolated and cultured. To assess the effect of AMPK on fibroblast migration, we conducted scratch and migration assays in NPDF treated with metformin and/or compound C. A collagen gel contraction assay measured activity of contractile. MMP expression was measured with reverse transcription-polymerase chain reaction, Western blot, and zymography. To evaluate for specific AMPK action, we examined by AMPK small interfering RNA. Results: Metformin, an activator of AMPK, significantly inhibited cell migration in NPDFs in a dose-dependent manner. Compound C, an inhibitor of AMPK, partially reversed the inhibitory effect of metformin. Metformin also significantly decreased contractile activity, with a concomitant reduction in the production of MMP-1 and MMP-2 but not of MMP-9. Specific silencing that targeted AMPK resulted in the enhancement of mobility and contractility and in the production of MMP-1 and MMP-2. Conclusion: AMPK played an important role in regulating cell migration, matrix contraction, and MMP production in NPDFs, which provided data that AMPK activator might be a therapeutic target for the prevention of tissue remodeling in nasal polyps.",

author = "Um, {Ji Young} and Lee, {Seoung Ae} and Park, {Joo Hoo} and Shin, {Jae Min} and Park, {Il Ho} and Lee, {Heung Man}",

note = "Funding Information: This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI15C1512) and by the Basic Science Research Program through the National Research Foundation of Korea, which is funded by the Ministry of Education (2013R1A1A2059716) Funding Information: 1 Reagents Seoul,Korea,2InstituteforIVDSupportcenterKoreaUniversityGuroHospital,KoreaFromtheDepartmentofBiomedicalScience,KoreaUniversity,CollegeofMedicine, Metformin and compound C were purchased from Sigma-Aldrich University,DCollege ofOMedicine, Seoul, Korea,N3Research-DrivenOHospital,TKorea Uni- CCo. (St. LOouis, MO).PTranswellsYl (Millipore Corp, Bedford, MA) were versityGuroHospital,KoreaUniversity,CollegeofMedicine,Seoul,SouthKorea,and purchased from Corning Life Sciences (Tewksbury, MA). 4Department of Otorhinolaryngology—Head and Neck Surgery, Korea University, J.Y.UmandS.A.LeecontributedequallytothisworkCollegeofMedicine,Seoul,Korea NPDF Culture ThisstudywassupportedbyagrantfromtheKoreanHealthTechnologyR&DProject, Six nasal polyp tissues (from three male and three female subjects) Ministry of Health & Welfare, Republic of Korea (HI15C1512) and by the Basic Science were collected from patients with chronic rhinosinusitis and nasal Research Program through the National Research Foundation of Korea, which is funded polyps who underwent endoscopic surgery in the Department of by the Ministry of Education (2013R1A1A2059716) Otorhinolaryngology. Some patients were excluded due to use of Theauthorshavenoconflictsofinteresttodeclarepertainingtothisarticle systemic steroids, immune modulatory drugs, or antibiotics within 4 AddresscorrespondencetoHeung-ManLee,M.D,DepartmentofOtorhinolaryngo- weeks before surgery, and a history of smoking. None of the patients logy—HeadandNeckSurgery,GuroHospital,KoreaUniversityCollegeofMedicine, had common allergies, asthma, or aspirin sensitivity. This study was E-mailaddress:lhman@korea.ac.kr148Guro-dongro,Guro-gu,Seoul08308,SouthKorea approved by the ethics committee of the Korea University Institu-Copyright{\textcopyright} 2017,OceanSidePublications,Inc.,U.S.A. tional Review Board at Korea University Medical Center with the principles of the Declaration of Helsinki (KUGGR-2010–015). Written Publisher Copyright: {\textcopyright} 2017, OceanSide Publications, Inc., U.S.A.",

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T1 - Role of adenosine monophosphate-activated protein kinase on cell migration, matrix contraction, and matrix metalloproteinase-1 and matrix metalloproteinase-2 production in nasal polyp-derived fibroblasts

AU - Um, Ji Young

AU - Lee, Seoung Ae

AU - Park, Joo Hoo

AU - Shin, Jae Min

AU - Park, Il Ho

AU - Lee, Heung Man

N1 - Funding Information: This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI15C1512) and by the Basic Science Research Program through the National Research Foundation of Korea, which is funded by the Ministry of Education (2013R1A1A2059716) Funding Information: 1 Reagents Seoul,Korea,2InstituteforIVDSupportcenterKoreaUniversityGuroHospital,KoreaFromtheDepartmentofBiomedicalScience,KoreaUniversity,CollegeofMedicine, Metformin and compound C were purchased from Sigma-Aldrich University,DCollege ofOMedicine, Seoul, Korea,N3Research-DrivenOHospital,TKorea Uni- CCo. (St. LOouis, MO).PTranswellsYl (Millipore Corp, Bedford, MA) were versityGuroHospital,KoreaUniversity,CollegeofMedicine,Seoul,SouthKorea,and purchased from Corning Life Sciences (Tewksbury, MA). 4Department of Otorhinolaryngology—Head and Neck Surgery, Korea University, J.Y.UmandS.A.LeecontributedequallytothisworkCollegeofMedicine,Seoul,Korea NPDF Culture ThisstudywassupportedbyagrantfromtheKoreanHealthTechnologyR&DProject, Six nasal polyp tissues (from three male and three female subjects) Ministry of Health & Welfare, Republic of Korea (HI15C1512) and by the Basic Science were collected from patients with chronic rhinosinusitis and nasal Research Program through the National Research Foundation of Korea, which is funded polyps who underwent endoscopic surgery in the Department of by the Ministry of Education (2013R1A1A2059716) Otorhinolaryngology. Some patients were excluded due to use of Theauthorshavenoconflictsofinteresttodeclarepertainingtothisarticle systemic steroids, immune modulatory drugs, or antibiotics within 4 AddresscorrespondencetoHeung-ManLee,M.D,DepartmentofOtorhinolaryngo- weeks before surgery, and a history of smoking. None of the patients logy—HeadandNeckSurgery,GuroHospital,KoreaUniversityCollegeofMedicine, had common allergies, asthma, or aspirin sensitivity. This study was E-mailaddress:lhman@korea.ac.kr148Guro-dongro,Guro-gu,Seoul08308,SouthKorea approved by the ethics committee of the Korea University Institu-Copyright© 2017,OceanSidePublications,Inc.,U.S.A. tional Review Board at Korea University Medical Center with the principles of the Declaration of Helsinki (KUGGR-2010–015). Written Publisher Copyright: © 2017, OceanSide Publications, Inc., U.S.A.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Purpose: Activation of adenosine monophosphate-activated protein kinase (AMPK) by metformin, as a master regulator of metabolism, is involved in airway tissue remodeling. Here, we investigated the physical role of AMPK on cell migration, matrix contraction, and the production of matrix metalloproteinases (MMP) in nasal polyp- derived fibroblasts (NPDF). Methods: Primary NPDFs from six patients with chronic rhinosinusitis and nasal polyps were isolated and cultured. To assess the effect of AMPK on fibroblast migration, we conducted scratch and migration assays in NPDF treated with metformin and/or compound C. A collagen gel contraction assay measured activity of contractile. MMP expression was measured with reverse transcription-polymerase chain reaction, Western blot, and zymography. To evaluate for specific AMPK action, we examined by AMPK small interfering RNA. Results: Metformin, an activator of AMPK, significantly inhibited cell migration in NPDFs in a dose-dependent manner. Compound C, an inhibitor of AMPK, partially reversed the inhibitory effect of metformin. Metformin also significantly decreased contractile activity, with a concomitant reduction in the production of MMP-1 and MMP-2 but not of MMP-9. Specific silencing that targeted AMPK resulted in the enhancement of mobility and contractility and in the production of MMP-1 and MMP-2. Conclusion: AMPK played an important role in regulating cell migration, matrix contraction, and MMP production in NPDFs, which provided data that AMPK activator might be a therapeutic target for the prevention of tissue remodeling in nasal polyps.

AB - Purpose: Activation of adenosine monophosphate-activated protein kinase (AMPK) by metformin, as a master regulator of metabolism, is involved in airway tissue remodeling. Here, we investigated the physical role of AMPK on cell migration, matrix contraction, and the production of matrix metalloproteinases (MMP) in nasal polyp- derived fibroblasts (NPDF). Methods: Primary NPDFs from six patients with chronic rhinosinusitis and nasal polyps were isolated and cultured. To assess the effect of AMPK on fibroblast migration, we conducted scratch and migration assays in NPDF treated with metformin and/or compound C. A collagen gel contraction assay measured activity of contractile. MMP expression was measured with reverse transcription-polymerase chain reaction, Western blot, and zymography. To evaluate for specific AMPK action, we examined by AMPK small interfering RNA. Results: Metformin, an activator of AMPK, significantly inhibited cell migration in NPDFs in a dose-dependent manner. Compound C, an inhibitor of AMPK, partially reversed the inhibitory effect of metformin. Metformin also significantly decreased contractile activity, with a concomitant reduction in the production of MMP-1 and MMP-2 but not of MMP-9. Specific silencing that targeted AMPK resulted in the enhancement of mobility and contractility and in the production of MMP-1 and MMP-2. Conclusion: AMPK played an important role in regulating cell migration, matrix contraction, and MMP production in NPDFs, which provided data that AMPK activator might be a therapeutic target for the prevention of tissue remodeling in nasal polyps.

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Role of adenosine monophosphate-activated protein kinase on cell migration, matrix contraction, and matrix metalloproteinase-1 and matrix metalloproteinase-2 production in nasal polyp-derived fibroblasts

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