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Insights Into the Mechanism of Action of 13-Cis Retinoic Acid

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Insights Into the Mechanism of Action of 13-Cis Retinoic Acid The Pennsylvania State University The Graduate School College of Medicine INSIGHTS INTO THE MECHANISM OF ACTION OF 13-CIS RETINOIC ACID IN SUPPRESSING SEBACEOUS GLAND FUNCTION A Thesis in Molecular Medicine by Amanda Marie Nelson © 2007 Amanda Marie Nelson Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 2007 The thesis of Amanda Marie Nelson was reviewed and approved* by the following: Diane M. Thiboutot Professor of Dermatology Thesis Advisor Chair of Committee Gary A. Clawson Professor of Pathology, Biochemistry and Molecular Biology Mark Kester Distinguished Professor of Pharmacology Jeffrey M. Peters Associate Professor of Molecular Toxicology Jong K. Yun Assistant Professor of Pharmacology Craig Meyers Professor of Microbiology and Immunology Co-chair, Molecular Medicine Graduate Degree Program *Signatures are on file in the Graduate School iii ABSTRACT Nearly 40-50 million people of all races and ages in the United States have acne, making it the most common skin disease. Although acne is not a serious health threat, severe acne can lead to disfiguring, permanent scarring; increased anxiety; and depression. Isotretinoin (13-cis Retinoic Acid) is the most potent agent that affects each of the pathogenic features of acne: 1) follicular hyperkeratinization, 2) the activity of Propionibacterium acnes, 3) inflammation and 4) increased sebum production. Isotretinoin has been on the market since 1982 and even though it has been prescribed for 25 years, extensive studies into its molecular mechanism of action in human skin and sebaceous glands have not been done. Since isotretinoin is a teratogen, there is a clear need for safe and effective alternative therapeutic agents. The studies undertaken in this thesis were designed to increase our understanding of the effects of 13-cis RA on the sebaceous gland and its mechanism of action in sebum suppression. It is well established that isotretinoin drastically reduces the size and lipid secretion of sebaceous glands. We hypothesized that isotretinoin decreases the size of the sebaceous gland by inducing cell cycle arrest and/or apoptosis and that sebum suppression is most likely an indirect result of the reduced size of the sebaceous gland. Our studies show that 13-cis RA, unlike 9-cis RA or ATRA, induces cell cycle arrest and apoptosis in SEB-1 sebocytes. Its ability to induce apoptosis is not inhibited in the presence of functional retinoic acid receptor (RAR) pan antagonist AGN 193198, suggesting an RAR- independent mechanism of apoptosis. Gene expression analysis was performed in cultured SEB-1 sebocytes that were treated with 13-cis RA and in biopsies of skin taken from patients that were treated for one week with isotretinoin. These data indicate that 13-cis RA increases expression of neutrophil gelatinase associated lipocalin (NGAL) and Tumor Necrosis Factor related apoptosis inducing ligand (TRAIL). In turn, we report that both NGAL and TRAIL induce apoptosis within SEB-1 sebocytes and, as such, are potential mediators of 13-cis RA induced apoptosis in human sebocytes. These studies into the mechanism of action of 13-cis RA in sebaceous glands suggest that 13-cis RA mediates its sebosuppressive effect through preferential induction of apoptosis in sebaceous glands. Furthermore, these data provide a rationale for drug discovery of alternative agents that are capable of selectively inducing apoptosis in sebaceous glands as a treatment for severe acne. iv TABLE OF CONTENTS LIST OF FIGURES ....................................................................................................ix LIST OF TABLES.......................................................................................................xvi LIST OF ABBREVIATIONS .......................................................................................xvii ACKNOWLEDGEMENTS ..........................................................................................xx Chapter 1 Literature Review .....................................................................................1 1.1 Introduction ...................................................................................................1 1.2 Sebaceous gland anatomy and physiology ..................................................1 1.2.1 Skin.....................................................................................................2 1.2.2 Anatomy of the Sebaceous Gland ......................................................3 1.2.2.1 Histology ...................................................................................3 1.2.2.2 Location ....................................................................................4 1.2.2.3 Embryogenesis and Morphogenesis ........................................5 1.2.2.4 Physiology of the Sebaceous Gland: Holocrine Secretion .......6 1.2.2.5 Lipid Composition of Sebum.....................................................7 1.2.2.6 Function of Sebum....................................................................7 1.2.3 Regulation of sebaceous gland size and sebum production...............8 1.3 Acne..............................................................................................................10 1.3.1 Epidemiology ......................................................................................10 1.3.2 Pathophysiology .................................................................................11 1.3.3 Classifications of acne lesions............................................................13 1.3.4 Model systems for acne research-animal ...........................................14 1.3.4.1 Rat preputial gland....................................................................14 1.3.4.2 Hamster flank organ and ear ....................................................15 1.3.4.3 Rhino mouse.............................................................................16 1.3.5 Models for acne research: isolated human sebaceous gland organ culture. ..................................................................................................17 1.3.6 Model systems for acne research: sebocyte cell culture ....................18 1.3.7 Current Treatments for Acne ..............................................................19 1.3.7.1 Cleansers: follicular hyperkeratinization ...................................19 1.3.7.2 Antibiotics: P. acnes and inflammation .....................................20 1.3.7.3 Hormonal therapy: sebum suppression ....................................20 1.3.7.4 Topical Retinoids: inflammation, follicular hyperkeratinization..22 1.3.7.5 Oral Retinoid: Isotretinoin (Accutane®, 13-cis Retinoic Acid)....22 1.4 Retinoids.......................................................................................................24 1.4.1 Retinoid Biology..................................................................................25 1.4.1.1 What are retinoids?...................................................................25 1.4.1.2 Retinoid receptors.....................................................................26 1.4.1.3 Retinoid binding proteins and retinoid metabolizing enzymes..28 1.4.1.4 Retinoid Function......................................................................30 1.4.1.4.1 Proliferation.....................................................................30 1.4.1.4.2 Differentiation..................................................................32 1.4.1.4.3 Apoptosis........................................................................33 1.5 Retinoids in dermatology ..............................................................................36 v 1.5.1 Significance of research project..........................................................36 Chapter 2 13-cis Retinoic Acid Induces Apoptosis and Cell Cycle Arrest in Human SEB- 1 Sebocytes ........................................................................................................37 2.1 Chapter Abstract...........................................................................................37 2.2 Introduction ...................................................................................................38 2.3 Results..........................................................................................................39 2.3.1 13-cis RA exhibits a more rapid onset of growth inhibition of SEB-1 sebocytes compared to 9-cis RA and ATRA. .......................................39 2.3.2 13-cis RA significantly inhibits DNA synthesis in SEB-1 sebocytes....41 2.3.3 13-cis RA, but not 9-cis RA or ATRA, increases p21 levels in SEB-1 sebocytes..............................................................................................43 2.3.4 13-cis RA, but not 9-cis RA or ATRA, decreases cyclin D1 protein in SEB- 1 sebocytes...........................................................................................45 2.3.5 13-cis RA induces apoptosis in SEB-1 sebocytes but not in HaCaT keratinocytes or NHEK. ........................................................................45 2.3.6 13-cis RA specifically increases levels of cleaved caspase 3 in SEB-1 sebocytes..............................................................................................47 2.3.7 13-cis RA, but not 9-cis RA or ATRA, increases TUNEL staining in SEB-1 sebocytes..............................................................................................49 2.3.8 Apoptosis induction by 13-cis RA in SEB-1 sebocytes is not blocked by RAR antagonist
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