Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells

Corcoran, Ryan B.; Scott, Matthew P.

doi:10.1073/pnas.0602852103

Cited by 292 publications

(283 citation statements)

References 36 publications

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“…Thus, cholesterol depletion acts at the level of Smo, or theoretically between Ptch1 and Smo. Subsequently, Corcoran et al showed that various pharmacologic inhibitors of the sterol synthesis pathway, including statins, could decrease cellular proliferation and Gli1 expression in a medulloblastoma cell line derived from Ptch1+/− p53−/− mice (PZp53 MED ) (Corcoran and Scott, 2006). This indicated that cholesterol or a cholesterol derivative was required for Shh signal transduction and proliferation.…”

Section: Sterols Activate Shh Signal Transductionmentioning

confidence: 99%

“…Therefore, there is evidence that Ptch1 regulates Smo catalytically (Taipale et al, 2002). Ptch1 is related to the resistance-nodulation-cell division (RND) family of bacterial pumps and to the Niemann-Pick C1 cholesterol transporter that is capable of transporting hydrophobic small molecules, including cholesterol (Corcoran and Scott, 2006;Taipale et al, 2002). It is possible that Smo activity is regulated by an endogenous small molecule rather than by direct proteinprotein interactions (Chen et al, 2002a).…”

Section: Smo: the Target Of Small Molecule Inhibitors Of The Shh Pathwaymentioning

confidence: 99%

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Novel Hedgehog pathway targets against basal cell carcinoma

Tang

Epstein

2007

Toxicology and Applied Pharmacology

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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, gastro-intestinal, 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. Epidemiology of Basal cell carcinoma (BCC)Basal cell carcinoma (BCC), the most common of all human cancers, affects close to 1 million Americans a year. Over the past 40 years there has been a dramatic increase in the incidence of BCC, and it is estimated that nearly 30% of Caucasians living in areas of high ambient sun exposure will develop a BCC (Miller and Weinstock, 1994). Furthermore, the incidence of BCC is rising in younger populations, especially among women (Christenson et al., 2005). Although the case fatality rate of BCCs is low, the high incidence and frequent occurrence of multiple primary tumors in affected individuals leads to significant morbidity. BCCs characteristically arise in sun-exposed body areas, most commonly on the head and neck, but also occur on the trunk and extremities. There are three accepted environmental insults for BCC development: ultraviolet radiation (UV), ionizing radiation (IR), and arsenic. Interindividual differences in the susceptibility to BCC development have been recognized for many years. Epidemiologic studies have identified phenotypic features such as fair skin and freckling tendency that are associated with an increased susceptibility to BCCs (Rubin et al., 2005).It is generally accepted that BCC can be caused by UV exposure from the sun. While the risk of squamous cell carcinoma is strongly related to cumulative sun exposure, sunlight's exact role in BCC development remains less clear (Armstrong and Kricker, 2001). Thus, epidemiologic studies have shown that BCC risk correlates better with intermittent sun exposure (i.e. childhood sunburns, weekend sun exposure) than with cumulative lifetime sun exposure (Corona et al., 2001). Hence, the timing, dose, and duration of UV exposure are critical to carcinogenesis, but UV seems to have a different role in SCC versus BCC carcinogenesis development. Consistent with this, a randomized clinical trial of daily sunscreen use showed that sunscreen reduced the incidence of SCC but not BCC. The daily application of an SPF 15 sunscreen to the head, neck, arms, and hands over a 4-5 year period had no e...

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Section: Sterols Activate Shh Signal Transductionmentioning

confidence: 99%

Section: Smo: the Target Of Small Molecule Inhibitors Of The Shh Pathwaymentioning

confidence: 99%

Novel Hedgehog pathway targets against basal cell carcinoma

Tang

Epstein

2007

Toxicology and Applied Pharmacology

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“…Of note, while the absolute upregulation of GLI1 in C3H10T1/2 cells was approximately 5-fold greater than in M2-10B4s, these absolute values correspond well with values previously reported for complete Hh activation. 4,5 To verify that the up-regulation of GLI1 and PTCH was the result of Hh pathway activation, we evaluated the ability of cyclopamine (Cyc), an Hh-specific inhibitor, to attenuate this response (Figure 2 …”

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confidence: 99%

Structure–Activity Relationships for Side Chain Oxysterol Agonists of the Hedgehog Signaling Pathway

Corman

DeBerardinis

Hadden

2012

ACS Med. Chem. Lett.

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Oxysterols (OHCs) are byproducts of cholesterol oxidation that are known to activate the Hedeghog (Hh) signaling pathway. While OHCs that incorporate hydroxyl groups throughout the scaffold are known, those that act as agonists of Hh signaling primarily contain a single hydroxyl on the alkyl side chain. We sought to further explore how side chain hydroxylation patterns affect oxysterol-mediated Hh activation, by performing a structure−activity relationship study on a series of synthetic OHCs. The most active analogue, 23(R)-OHC (35), demonstrated potent activation of Hh signaling in two Hh-dependent cell lines (EC 50 values 0.54−0.65 μM). In addition, OHC 35 was approximately 3-fold selective for the Hh pathway as compared to the liver X receptor, a nuclear receptor that is also activated by endogenous OHCs. Finally, 35 induced osteogenic differentiation and osteoblast formation in cultured cells, indicating functional agonism of the Hh pathway.

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“…Smo, a seven-pass transmembrane protein of the extended G-protein-coupled receptor family, has an active and an inactivate state that appears to be defined both by its location within the cell (inside or outside of the primary cilia) [31] and by other modifications that may include its ability to capture oxysterols at an active site [32,33]. Smo activation requires two steps that were operationally defined by certain low-molecular-weight compounds that disrupt the activation process [34].…”

Section: Overview Of the Hedgehog Signaling Pathwaymentioning

confidence: 99%

“…These include interference with hedgehog ligand processing, release or receptor binding by effectors of sterol biosynthesis [32] or direct interference with mature ligand function by the presence of the HIP protein that binds to ligands and prevents their interaction with receptors [48]. For the target cell, hedgehog signaling can be facilitated by the presence of heparin proteoglycans and lower affinity hedgehog coreceptor proteins that include CDON and BOC [49].…”

Section: Overview Of the Hedgehog Signaling Pathwaymentioning

confidence: 99%

Targeting the CB2 cannabinoid receptor in osteoporosis

Chen

Carkner

Buttyan

2011

Expert Review of Endocrinology & Metabolism

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Hedgehog is a ligand-activated signaling pathway that regulates Gli-mediated transcription. Although most noted for its role as an embryonic morphogen, hyperactive hedgehog also causes human skin and brain malignancies. The hedgehog-related gene anomalies found in these tumors are rarely found in prostate cancer. Yet surveys of human prostate tumors show concordance of high expression of hedgehog ligands and Gli2 that correlate with the potential for metastasis and therapy-resistant behavior. Likewise, prostate cancer cell lines express hedgehog target genes, and their growth and survival is affected by hedgehog/Gli inhibitors. To date, the preponderance of data supports the idea that prostate tumors benefit from a paracrine hedgehog microenvironment similar to the developing prostate. Uncertainty remains as to whether hedgehog’s influence in prostate cancer also includes aspects of tumor cell autocrine-like signaling. The recent findings that Gli proteins interact with the androgen receptor and affect its transcriptional output have helped to identify a novel pathway through which hedgehog/Gli might affect prostate tumor behavior and raises questions as to whether hedgehog signaling in prostate cancer cells is suitably measured by the expression of Gli target genes alone.

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Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells

Cited by 292 publications

References 36 publications

Novel Hedgehog pathway targets against basal cell carcinoma

Novel Hedgehog pathway targets against basal cell carcinoma

Structure–Activity Relationships for Side Chain Oxysterol Agonists of the Hedgehog Signaling Pathway

Targeting the CB2 cannabinoid receptor in osteoporosis

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