Novel Hedgehog pathway targets against basal cell carcinoma - PubMed (original) (raw)

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Novel Hedgehog pathway targets against basal cell carcinoma

Jean Y Tang et al. Toxicol Appl Pharmacol. 2007.

Abstract

The Hedgehog signaling pathway plays a key role in directing growth and patterning during embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin, and hair. Aberrant activation of the Hedgehog (Hh) pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and a subset of pancreatic, gastrointestinal, and other cancers. This review will provide an overview of what is known about the mechanisms by which activation of Hedgehog signaling leads to the development of BCCs and will review two recent papers suggesting that agents that modulate sterol levels might influence the Hh pathway. Thus, sterols may be a new therapeutic target for the treatment of BCCs, and readily available agents such as statins (HMG-CoA reductase inhibitors) or vitamin D might be helpful in reducing BCC incidence.

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Figures

Figure 1

Figure 1

Model of Hedgehog signaling in vertebrates. A. Ptch inhibits Smo in the absence of Hh. SMO is unable to activate Gli transcription factors as Sufu binds Gli and prevents the transcription of Hh target genes. Hh ligand is bound by Hip on the membrane surface. B. Binding of the Hh ligand inhibits Ptch, and relieves the inhibition of Smo by Ptch. Smo localizes to the membrane and is now able to activate Gli transcription factors. Hh target genes are transcribed.

Figure 2

Figure 2

Structural similarities between cholesterol, cyclopamine, 7-dehydrocholesterol (pro-vitamin D3), and vitamin D3

Figure 3

Figure 3

Two models for Ptch regulation of Smo activation by sterols based on Ptch homology to pump and transport proteins. (Adapted from Corcoran and Scott, 2006) A. Ptch could pump activating sterols (cholesterol, other oxysterols) away from Smo, preventing Smo activation. (Corcoran and Scott, 2006) B. Alternatively, Ptch could pump inhibitory sterols (vitamin D3) towards Smo. (Bijlsma and Peppelenbosch, 2006)

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