title: Progesterone receptor (PR) polyproline domain (PPD) mediates inhibition of epidermal growth factor receptor (EGFR) signaling in non-small cell lung cancer cells.
abstract: Recent evidence has suggested a possible role for progesterone receptor (PR) in the progression of non-small cell lung cancer (NSCLC). However, little is known concerning roles of PR in NSCLC. PR contains a polyproline domain (PPD), which directly binds to the SH3 domain of signaling molecules. Because PPD-SH3 interactions are essential for EGFR signaling, we hypothesized that the presence of PR-PPD interfered with EGFR-mediated signaling and cell proliferation. We examined the role of PR-PPD in cell proliferation and signaling by stably expressing PR-B, or PR-B with disrupting mutations in the PPD (PR-BΔSH3), from a tetracycline-regulated promoter in A549 NSCLC cells. PR-B dose-dependently inhibited cell growth in the absence of ligand, and progestin (R5020) treatment further suppressed the growth. Treatment with RU486 abolished PR-B- and R5020-mediated inhibition of cell proliferation. Expression of PR-BΔSH3 and treatment with R5020 or RU486 had no effect on cell proliferation. Furthermore, PR-B expression but not PR-BΔSH3 expression reduced EGF-induced A549 proliferation and activation of ERK1/2, in the absence of ligand. Taken together, our data demonstrated the significance of PR extranuclear signaling through PPD interactions in EGFR-mediated proliferation and signaling in NSCLC.
authors.affiliation: Department of Clinical Chemistry and Graduate Program in Clinical Biochemistry and Molecular Medicine, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Sornsawan
authors.initials: S
authors.lastname: Kawprasertsri
authors.affiliation: Jonsson Comprehensive Cancer Center and Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Pietras
authors.affiliation: Jonsson Comprehensive Cancer Center and Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Marquez-Garban
authors.affiliation: Department of Clinical Chemistry and Graduate Program in Clinical Biochemistry and Molecular Medicine, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand; Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Chulalongkorn University, Bangkok 10330, Thailand. Electronic address: Viroj.b@chula.ac.th.
authors.forename: Viroj
authors.initials: V
authors.lastname: Boonyaratanakornkit
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055232:Proline-Rich Protein Domains; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011980:Receptors, Progesterone; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; MAPK; Progesterone receptor; SH3 domain; lung cancer