Protein kinase A activation inhibits oncogenic Sonic hedgehog signalling and suppresses basal cell carcinoma of the skin.

Abstract:

:Basal cell carcinoma of the skin (BCC) is caused by constitutive activation of the Sonic hedgehog (Shh) pathway, mainly through mutations either in the Shh receptor Patched (PTCH) or in its co-receptor Smoothened (Smo). Inhibitors of this pathway that are currently in clinical trials inhibit Smo. However, mutations in Smo can result in resistance to these inhibitors. To target most BCCs and avoid acquired resistance because of Smo mutations, inhibiting the Shh-pathway downstream of Smo is critical. Attractive downstream targets would be at the level of Gli proteins, the transcriptional activators of this pathway in BCCs. Previously it has been shown that Gli1 and Gli2, when phosphorylated by protein kinase A (PKA), are targeted for proteosomal degradation. Here we show that PKA activation via the cAMP agonist forskolin is sufficient to completely abolish oncogenic Smo activity in vitro. In an inducible BCC mouse model due to a Smo mutation that confers resistance to current Smo inhibitors, topical forskolin treatment significantly reduced Gli1 mRNA levels and resulted in strongly suppressed BCC tumor growth. Our data show that forskolin inhibits the growth of even those BCCs that are resistant to Smo inhibitors and provide a proof-of-principle framework for the development of topically applied human skin-permeable novel pharmacologic inhibitors of oncogenic Shh-signaling through PKA activation.

journal_name

Exp Dermatol

journal_title

Experimental dermatology

authors

Makinodan E,Marneros AG

doi

10.1111/exd.12016

subject

Has Abstract

pub_date

2012-11-01 00:00:00

pages

847-52

issue

11

eissn

0906-6705

issn

1600-0625

journal_volume

21

pub_type

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