title: 9-cis-retinoic Acid and troglitazone impacts cellular adhesion, proliferation, and integrin expression in K562 cells.
abstract: Retinoids are established pleiotropic regulators of both adaptive and innate immune responses. Recently, troglitazone, a PPAR gamma agonist, has been demonstrated to have anti-inflammatory effects. Separately, retinoids and troglitazone are implicated in immune related processes; however, their combinatory role in cellular adhesion and proliferation has not been well established. In this study, the effect of 9-cis-retinoic acid (9-cis-RA) and troglitazone on K562 cellular adhesion and proliferation was investigated. Troglitazone exposure decreased K562 cellular adhesion to RGD containing extracellular matrix proteins fibronectin, FN-120, and vitronectin in a concentration and time-dependent manner. In the presence of troglitazone, 9-cis-retinoic acid restores cellular adhesion to levels comparable to vehicle treatment alone on fibronectin, FN-120, and vitronectin substrates within 72 hours. Due to the prominent role of integrins in attachment to extracellular matrix proteins, we evaluated the level of integrin α5 subunit expression. Troglitazone treatment results in decrease in α5 subunit expression on the cell surface. In the presence of both agonists, cell surface α5 subunit expression was restored to levels comparable to vehicle treatment alone. Additionally, troglitazone and 9-cis-RA mediated cell adhesion was decreased in the presence of a function blocking integrin alpha 5 inhibitor. Further, through retinoid metabolic profiling and HPLC analysis, our study demonstrates that troglitazone augments retinoid availability in K562 cells. Finally, we demonstrate that troglitazone and 9-cis-retinoic acid synergistically dampen cellular proliferation in K562 cells. Our study is the first to report that the combination of troglitazone and 9-cis-retinoic acid restores cellular adhesion, alters retinoid availability, impacts integrin expression, and dampens cellular proliferation in K562 cells.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Hanson
authors.affiliation: College of Medicine, University of Arkansas Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gambill
authors.affiliation: College of Medicine, University of Arkansas Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Venusa
authors.initials: V
authors.lastname: Phomakay
authors.affiliation: College of Pharmacy, Harding University, Searcy, Arkansas United States of America.
authors.forename: C Tyler
authors.initials: CT
authors.lastname: Staten
authors.affiliation: Department of Chemistry, University of Central Arkansas, Conway, Arkansas, United States of America.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Kelley
mesh_terms: D000077556:Alitretinoin; D001682:Biological Availability; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism*; D020014:K562 Cells; D009842:Oligopeptides / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*; D000077288:Troglitazone; D019096:Vitronectin / Q000378:metabolism
chemical_list: D002839:Chromans; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D039482:Integrin alpha5; D009842:Oligopeptides; D045162:Thiazolidinediones; D019096:Vitronectin; D000077556:Alitretinoin; D014212:Tretinoin; C047981:arginyl-glycyl-aspartic acid; D000077288:Troglitazone