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Protein kinase A activation inhibits oncogenic S onic hedgehog signalling and suppresses basal cell carcinoma of the skin
Author(s) -
Makinodan Eri,
Marneros Alexander G.
Publication year - 2012
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12016
Subject(s) - hedgehog signaling pathway , forskolin , vismodegib , protein kinase a , cancer research , basal cell carcinoma , signal transduction , kinase , hedgehog , sonic hedgehog , cyclopamine , phosphorylation , microbiology and biotechnology , smoothened , biology , chemistry , receptor , medicine , biochemistry , basal cell
Basal cell carcinoma of the skin ( BCC ) is caused by constitutive activation of the S onic hedgehog ( S hh) pathway, mainly through mutations either in the S hh receptor P atched ( PTCH ) or in its co‐receptor S moothened ( S mo). Inhibitors of this pathway that are currently in clinical trials inhibit S mo. However, mutations in S mo can result in resistance to these inhibitors. To target most BCC s and avoid acquired resistance because of S mo mutations, inhibiting the S hh‐pathway downstream of S mo is critical. Attractive downstream targets would be at the level of G li proteins, the transcriptional activators of this pathway in BCC s. Previously it has been shown that G li1 and G li2, when phosphorylated by protein kinase A ( PKA ), are targeted for proteosomal degradation. Here we show that PKA activation via the c AMP agonist forskolin is sufficient to completely abolish oncogenic S mo activity in vitro . In an inducible BCC mouse model due to a S mo mutation that confers resistance to current S mo inhibitors, topical forskolin treatment significantly reduced G li1 m RNA levels and resulted in strongly suppressed BCC tumor growth. Our data show that forskolin inhibits the growth of even those BCC s that are resistant to S mo inhibitors and provide a proof‐of‐principle framework for the development of topically applied human skin‐permeable novel pharmacologic inhibitors of oncogenic S hh‐signaling through PKA activation.