title: Inhibition of the prohormone convertase subtilisin-kexin isoenzyme-1 induces apoptosis in human melanoma cells.
abstract: Prohormone convertases (PCs) are endoproteases that process many substrates in addition to hormone precursors. Although overexpression of PCs is linked to carcinogenesis in some solid tumors, the role of subtilisin-kexin isoenzyme-1 (SKI-1) in this context is unknown. We show that SKI-1 is constitutively expressed in human pigment cells with higher SKI activity in seven out of eight melanoma cell lines compared with normal melanocytes. SKI-1 immunoreactivity is also detectable in tumor cells of melanoma metastases. Moreover, tissue samples of the latter display higher SKI-1 mRNA levels and activity than normal skin. From various stimuli tested, 12-O-tetradecanoylphorbol-13-acetate and tunicamycin affected SKI-1 expression. Importantly, SKI-1 inhibition by the cell-permeable enzyme inhibitor decanoyl-RRLL-chloromethylketone (dec-RRLL-CMK) not only suppressed proliferation and metabolic activity of melanoma cells in vitro but also reduced tumor growth of melanoma cells injected intracutaneously into immunodeficient mice. Mechanistic studies revealed that dec-RRLL-CMK induces classical apoptosis of melanoma cells in vitro and affects expression of several SKI-1 target genes including activating transcription factor 6 (ATF6). However, ATF6 gene silencing does not result in apoptosis of melanoma cells, suggesting that dec-RRLL-CMK induces cell death in an ATF6-independent manner. Our findings encourage further studies on SKI-1 as a potential target for melanoma therapy.
authors.affiliation: Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, Department of Dermatology, University of Münster, Münster, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Weiß
authors.affiliation: Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, Department of Dermatology, University of Münster, Münster, Germany.
authors.forename: Agatha
authors.initials: A
authors.lastname: Stegemann
authors.affiliation: Clinical and Experimental Dermatology/Department of Biomedical Sciences, University of Bradford, Yorkshire, UK.
authors.forename: Marwa A T
authors.initials: MAT
authors.lastname: Elsayed
authors.affiliation: Clinical and Experimental Dermatology/Department of Biomedical Sciences, University of Bradford, Yorkshire, UK; Institute for Pigmentary Disorders in Association with the E.M. Arndt University of Greifswald, Greifswald, Germany.
authors.forename: Karin U
authors.initials: KU
authors.lastname: Schallreuter
authors.affiliation: Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, Department of Dermatology, University of Münster, Münster, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Luger
authors.affiliation: Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, Department of Dermatology, University of Münster, Münster, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Loser
authors.affiliation: Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, Department of Dermatology, University of Münster, Münster, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Metze
authors.affiliation: Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, Department of Dermatology, University of Münster, Münster, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Weishaupt
authors.affiliation: Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, Department of Dermatology, University of Münster, Münster, Germany. Electronic address: bohmm@uni-muenster.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Böhm
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary*; D051379:Mice; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000590:Amino Acid Chloromethyl Ketones; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1