Protein kinase A activation inhibits oncogenic S onic hedgehog signalling and suppresses basal cell carcinoma of the skin
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 inh...
Gespeichert in:
Veröffentlicht in: | Experimental dermatology 2012-11, Vol.21 (11), p.847-852 |
---|---|
Hauptverfasser: | , |
Format: | Artikel |
Sprache: | eng |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | 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. |
---|---|
ISSN: | 0906-6705 1600-0625 |
DOI: | 10.1111/exd.12016 |