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    Inhibition of the prohormone convertase subtilisin-kexin isoenzyme-1 induces apoptosis in human melanoma cells

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    Publication date
    2014
    Author
    Weiß, N.
    Stegemann, A.
    Elsayed, Marwa A.T.A.
    Schallreuter, Karin U.
    Luger, T.A.
    Loser, K.
    Metze, D.
    Weishaupt, C.
    Böhm, M.
    Keyword
    Prohormone convertases; PCs; Endoproteases; Apoptosis; Human melanoma cells; Melanoma therapy
    Peer-Reviewed
    Yes
    
    Metadata
    Show full item record
    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.
    URI
    http://hdl.handle.net/10454/7065
    Version
    No full-text available in the repository
    Citation
    Weiß N, Stegemann A, Elsayed MA, Schallreuter KU, Luger TA, Loser K, Metze D, Weishaupt C and Böhm M (2014) Journal of Investigative Dermatology. 134 (1):168-75.
    Link to publisher’s version
    http://dx.doi.org/10.1038/jid.2013.282
    Type
    Article
    Collections
    Life Sciences Publications

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