title: Alterations in cholesterol sulfate and its biosynthetic enzyme during multistage carcinogenesis in mouse skin.
abstract: Recent evidence suggests that cholesterol sulfate may be an important second messenger involved in signaling epidermal differentiation in skin. The activity of cholesterol sulfotransferase (Ch-ST) is increased during squamous differentiation of keratinocytes and is believed to be a marker enzyme for terminal differentiation. The primary objective of this study was to examine changes in levels of cholesterol sulfate (CS) and activity of its biosynthetic enzyme, Ch-ST, during multistage carcinogenesis in mouse skin. Using SENCAR mice, we determined the activity of Ch-ST in normal epidermis, in tumor promoter-treated epidermis, in epidermis during wound healing, and in mouse skin tumors generated by initiation-promotion regimens. A single topical application of tumor promoters led to significantly elevated levels of Ch-ST activity and of CS. Epidermal Ch-ST activity was also elevated during wound healing. Dramatic increases in CS levels and in the activity of Ch-ST were found in nearly all of the papillomas and squamous cell carcinomas examined. The increased levels of CS and activity of Ch-ST in tumor promoter-treated epidermis were accompanied by increased transglutaminase-I activity. In contrast, transglutaminase I activity was not elevated in primary papillomas or squamous cell carcinomas. Finally, Ch-ST activity was significantly elevated in the epidermis of newborn HK1.ras transgenic mice, whereas transglutaminase I activity did not correlate with Ch-ST activity in these mice. These results demonstrate that diverse tumor-promoting stimuli all produce elevated CS levels and Ch-ST activity and that CS levels and Ch-ST activity were constitutively elevated in both papillomas and squamous cell carcinomas. The data also suggest a mechanism for upregulation of Ch-ST in skin tumors involving activation/upregulation of Ha-ras.
authors.affiliation: Department of Carcinogenesis, The University of Texas, M.D. Anderson Cancer Center, Smithville 78957, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kiguchi
authors.forename: M
authors.initials: M
authors.lastname: Kagehara
authors.forename: R
authors.initials: R
authors.lastname: Higo
authors.forename: M
authors.initials: M
authors.lastname: Iwamori
authors.forename: J
authors.initials: J
authors.lastname: DiGiovanni
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002788:Cholesterol Esters / Q000378:metabolism*; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D004817:Epidermis / Q000187:drug effects / Q000201:enzymology; D005260:Female; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D018632:Mice, Inbred SENCAR; D008822:Mice, Transgenic; D019319:Okadaic Acid / Q000494:pharmacology; D012878:Skin Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism*; D015238:Sulfotransferases / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D011503:Transglutaminases / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
chemical_list: D000873:Anthracenes; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D002788:Cholesterol Esters; D019319:Okadaic Acid; D019314:Dehydroepiandrosterone Sulfate; C013883:chrysarobin; D011503:Transglutaminases; D015238:Sulfotransferases; C043456:cholesterol sulfotransferase; C007045:cholesteryl sulfate; D013755:Tetradecanoylphorbol Acetate