title: RARα/RXR synergism potentiates retinoid responsiveness in cutaneous T-cell lymphoma cell lines.
abstract: Retinoids, natural and synthetic derivatives of vitamin A, induce cellular changes by activating nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR). Although the ability of retinoids to govern gene expression is exploited clinically for cancer therapeutics, the full benefit of retinoid-based strategies is unrealized due to detrimental side effects. Delineating the receptors that prompt cellular outcomes is critical to advancing retinoid-based approaches. Here, we identify the receptors that evoke multiple responses in cutaneous T-cell lymphoma (CTCL). The data demonstrate that RARα drives integrin β7-dependent adhesion and CCR9-mediated chemotaxis in CTCL cells. Of note, concomitant activation of RARα and RXR nuclear receptors yielded synergistic increases in adhesion and migration at concentrations where single agents were ineffective. As the established paradigm of retinoid action in CTCL is apoptosis and growth arrest, the role of RARα/RXR in these events was studied. As with adhesion and migration, RARα/RXR synergism prompted apoptosis and dampened CTCL cell proliferation. Strikingly, RARα/RXR synergism induced responses from CTCL cell lines previously reported to be unresponsive to retinoids. These data provide a novel framework that may further refine a proven CTCL therapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Sebastian S
authors.initials: SS
authors.lastname: DeMarco
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Mary Stuart
authors.initials: MS
authors.lastname: Peaks
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Maiorana-Boutilier
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: JianMing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Miranda J
authors.initials: MJ
authors.lastname: Crouch
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Shewchuk
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Saame Raza
authors.initials: SR
authors.lastname: Shaikh
authors.affiliation: Department of Internal Medicine, Dermatology Division, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Phillips
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.|Biochemistry, Molecular and Cell Sciences, Arkansas College of Osteopathic Medicine, Arkansas Colleges of Health Education, Ft. Smith, AR, USA.
authors.forename: Lance C
authors.identifier: 0000-0003-2483-5064
authors.initials: LC
authors.lastname: Bridges
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology; D000077610:Bexarotene; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D015870:Gene Expression; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha / Q000819:agonists / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D001565:Benzoates; D039641:Integrin beta Chains; D012333:RNA, Messenger; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; C091368:integrin beta7; C068073:Am 580; D014212:Tretinoin; D000077610:Bexarotene
keywords: chemotaxis; integrin; lymphoma; retinoid; vitamin A