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Acta Biochim Biophys
Sin 2008, 40: 670-680
doi:10.1111/j.1745-7270.2008.00431.x
Implications of hedgehog signaling
antagonists for cancer therapy
Jingwu Xie*
Department of Pharmacology and Toxicology,
Sealy Center for Cancer Cell Biology, University of Texas at Galveston,
Galveston, Texas 77555-1048, USA
Received: April 15,
2008
Accepted: April 28,
2008
This work was
supported by the grants from the National Cancer Institute (CA94160, DOD
PC030429) and the AGA Foundation
*Corresponding
author: Tel, 1-409-747-1845; Fax, 1-409-747-1938; E-mail, [email protected]
The hedgehog (Hh) pathway, initially
discovered in Drosophila by two Nobel laureates, Dr. Eric Wieschaus and
Dr. Christiane Nusslein-Volhard, is a major regulator for cell differentiation,
tissue polarity and cell proliferation. Studies from many laboratories, including
ours, reveal activation of this pathway in most basal cell carcinomas and in
approximately 30% of extracutaneous human cancers, including medulloblastomas,
gastrointestinal, lung, breast and prostate cancers. Thus, it is believed that
targeted inhibition of Hh signaling may be effective in treating and preventing
many types of human cancers. Even more exciting is the discovery and synthesis
of specific signaling antagonists for the Hh pathway, which have significant
clinical implications in novel cancer therapeutics. This review discusses the
major advances in the current understanding of Hh signaling activation in
different types of human cancers, the molecular basis of Hh signaling
activation, the major antagonists for Hh signaling inhibition and their
potential clinical application in human cancer therapy.
Keywords hedgehog; smoothened; PTCH1;
human cancer therapy; basal cell carcinoma; antagonist
The hedgehog (Hh) gene was identified by two Nobel
laureates through genetic analysis of segmentation of fruit fly Drosophila [1].
In the early 1990s, three homologs of the Hh gene were identified in
vertebrates [2–6]. As an essential developmental signaling
pathway, the Hh pathway is critical for maintaining tissue polarity and stem
cell population. Inactivation of this pathway causes developmental defects such
as holoprosencephaly [7]. Hyperactivation of this pathway is found in most
basal cell carcinomas (BCCs) and many extracutaneous cancers [8–10]. The emerging role of Hh signaling in
human cancer further emphasizes the importance of studying this pathway.
Current Understanding of Hh Signaling
Mechanisms
Overall, the general signaling mechanisms of the Hh pathway is
conserved from fly to human [11]. The seven transmembrane domain containing the
protein smoothened (SMO) serves as the key player for signal transduction of
this pathway. However, the pathways function is inhibited by another
transmembrane protein, patched (PTC), in the absence of Hh ligands. In the
presence of active Hh ligands, binding of Hh to its receptor PTC releases this
inhibition, allowing SMO to signal downstream to Gli transcription factors. As
transcription factors, Gli molecules can regulate target gene expression by directly
associating with a specific consensus sequence located in the promoter region
of the target genes [12,13]. Fig. 1 shows the simplified diagram of Hh
signaling in the presence or absence of Hh. Hh proteins [one Hh in Drosophila and three Hhs in vertebrates:
sonic hedgehog (Shh), Indian hedgehog (Ihh) and desert hedgehog (Dhh)] are
secreted molecules, functioning both on nearby and distant cells in developing
tissues. Following translation, Hh proteins enter the secretory pathway and
undergo autoprocessing and lipid modification reactions
that produce a signaling peptide modified at both ends by
palmitoyl (N-terminus) and cholesteryl (C-terminus) adducts
[14–16].
The movement of Hh proteins is regulated by several molecules: Dispatched (Disp), the transmembrane transporter-like protein for release of Hh
from secreting cells [1114]; Dally-like (Dlp) and Dally, heparan sulfate proteoglycans for extracellular transport of Hh
protein [15]; and enzymes, such as sulfateless and
tout-velu, for heparan sulfate biosynthesis [17–19]. PTC [one PTC in flies and two PTCs in vertebrates: patched homolog 1
(PTCH1) and patched homolog 2 (PTCH2)] is the major receptor for Hh proteins
[20]. Several molecules are involved in regulating Hh reception. Hh-interacting
protein (HIP) can compete with PTC in binding Hh, thus preventing Hh signaling
[21]. Recent studies indicate that two additional molecules, Cdo and Gas1, are
also required for Hh binding [22–28]. It is still not entirely clear how
binding of Hh proteins results in pathway activation. One hypothesis is that,
in the absence of Hh, PTC normally inhibits the function of SMO. Binding of Hh
proteins to the receptor PTC releases PTC-mediated inhibition on SMO, thus SMO
can signal to downstream molecules. Very little is known about signaling events
immediately downstream of SMO. In Drosophila, several laboratories have
shown that SMO accumulation is promoted through protein phosphorylation at the
C-terminus by protein kinase A (PKA) and casein kinase I [29,30]. SMO mutants
lacking these phosphorylation sites are defective in Hh signaling. However,
these phosphorylation sites are not conserved in vertebrate SMO, indicating a
different mechanism for SMO signaling in higher organisms [30].
Accumulated evidence from several groups indicates
that the primary cilia found on most vertebrate cells play an important but
undefined role in the Hh pathway [31–35].
Functions of the primary cilium is regulated by large protein complexes
involved in intraflagellar transport (IFT), which functions in retrograde and
anterograde movement of cargo within the primary cilia [36]. A number of
mutations encoding IFT proteins involved in the primary cilium anterograde IFT
have been described, resulting in mice with Hh loss of function phenotypes
[32]. Several Hh components, including SMO and Gli molecules, are also present
at the primary cilium upon Hh stimulation [37]. A SMO mutant lacking ciliary
translocation blocks Hh signaling [31]. Gli3 processing is significantly
affected by IFT mutants [33,34], suggesting that SMO activates downstream
molecules at the cilium. However, it is not clear how SMO is transported to the
cilium in response to Hh signaling and how SMO activates downstream effectors.
Evidence suggests that SMO is endocytosed and can be degraded in the lysosomes
[38]. In cultured mammalian cells, both SMO and PTCH1 are internalized and
localized to endosomes, and Hh induces segregation of SMO-containing vehicles
from Hh-PTCH1 complexes destined for lysosomal degradation [38]. It is not
clear how SMO endocytosis is regulated.
Based on studies of Drosophila, there are several molecules,
including COS2 and Fused, genetically downstream of SMO signaling, but the
functions of their vertebrate homologs in Hh signaling remains to be established.
Inactivation of vertebrate homologs of COS2, KIF27 and KIF7, do not affect Hh
signaling in cultured mammalian cells [39], which suggests that KIF7 and KIF27
may not be required for Hh signaling. Because the homology between COS2 and
KIFs is very low, it is possible that a few molecules replace the function of
COS2 in vertebrates. Alternatively, SMO signaling in vertebrates may utilize a
distinct mechanism. Additional evidence from knockout mice with each of these KIF
genes should provide insight into the in vivo roles of these COS2
homologs. Another surprise is that knockout of the vertebrate homolog of Fused
can survive for up to two weeks but die of hydrocephalus [40,41]. No change of
Hh signaling is seen in these knockout mice, suggesting that Fused is not
critical for Hh signaling in early embryonic development. Based on these
studies, however, one can not ignore the possibility that Fused is only
partially involved in Hh signaling. Several novel cytoplasmic regulators of Hh signaling, including Rab23
and tectonic [42,43], have been identified as being unique to mammalian cells.
Both Rab23 and tectonic are negative regulators of Hh signaling downstream of
SMO, but the exact interacting partners are not clear. Unlike many Rab
proteins, Rab23 expresses both in the nucleus and cytoplasm (our unpublished
observation), suggesting that Rab23 may have other functions besides membrane
trafficking. The negative regulatory functions of suppressor of Fused [Su(Fu)] in
vertebrates, in contrast, are enhanced in mammals. Su(Fu) in Drosophila
was originally identified genetically by its ability to suppress active Fused
mutations, but it is not itself required for pathway activity. Several recent
studies suggest that Su(Fu) plays a key negative regulatory role in Hh
signaling. Su(Fu) null mouse mutants not only fail to repress the pathway [44],
but have similar phenotypes as inactivation of the other key negative regulator
acting upstream, PTCH1. Moreover, Su(Fu) null MEFs and wild-type cells
treated with Su(Fu) short interfering RNAs display Hh pathway activation,
supporting a central role in pathway repression [44]. The skin phenotype of
Su(Fu)+/– mice is as severe as the PTCH+/– mice, the latter is a classic model for tumor suppressor function in
the Hh pathway. At the molecular level, Su(Fu) is shown to associate directly
with and to inhibit Gli molecules, though the details are unclear [45].Ultimately, Hh signaling is transduced to downstream Gli
transcription factors, which can regulate target gene expression by direct
association with a consensus binding site (5‘-TGGGTGGTC-3‘)
located in the promoter region of the target genes [12,13,46,47]. There are
several ways to regulate the activity of Gli transcription factors. First,
nuclear-cytoplasmic shuttling of Gli molecules is tightly regulated [45,48–50]. For
example, PKA is shown to retain Gli1 proteins in the cytoplasm (through a PKA
site in the nuclear localization signal peptide) [48], whereas active Ras
signaling promotes Gli nuclear localization [50]. Second, ubiquitination and
protein degradation of Gli molecules is also regulated by several distinct
mechanisms, including TrCP, Cul3/BTB and Numb/Itch [51–55]. In addition to protein
degradation, Gli3 and Gli2, to a lesser extent, can be processed into
transcriptional repressors, which may be mediated by the TrCP E3 ligase [53].
Defects in the retrograde motor for IFT are also shown to affect Gli3
processing [56]. Fourth, transcriptional activity of Gli molecules is also
tightly regulated. It is reported that EGF can synergize with Gli transcription
factors to regulate target gene expression [57]. Su(Fu) not only prevents
nuclear translocation of Gli molecules, but it also inhibits Gli1-mediated
transcriptional activity [58]. Table 1 summarizes the major components
of the Hh pathway in vertebrates.
There are several feedback regulatory loops in this pathway. PTC,
Hh-interacting protein (HIP), Gas1 and Gli1, which are components of this
pathway, are also the target genes. PTC and HIP provide negative feedback
mechanisms to maintain the pathway activity at an appropriate level in a given
cell. In contrast, Gli1 forms a positive regulatory loop. Gas1 is
down-regulated by the Hh pathway, but it is positively involved in Hh
signaling. Alteration of these loops, such as loss of PTCH1 in BCCs, likely
results in abnormal signaling of this pathway.
Activation of the Hh Pathway in Human
Cancers
The major breakthrough in our understanding of Hh signaling in human
cancers came from the discovery that mutations of the human homolog of the Drosophila
patched gene (PTCH1) are associated with a rare hereditary form of BCC:
basal cell nevus syndrome (also called Gorlin syndrome) [59–61]. PTCH1 is
the receptor for Hh proteins, and previous studies have indicated that PTCH1
mainly functions in embryonic development.The major breakthrough in our understanding of Hh signaling in human
cancers came from the discovery that mutations of the human homolog of the Drosophila
patched gene (PTCH1) are associated with a rare hereditary form of BCC:
basal cell nevus syndrome (also called Gorlin syndrome) [59–61]. PTCH1 is
the receptor for Hh proteins, and previous studies have indicated that PTCH1
mainly functions in embryonic development.
Mutations of PTCH1 in basal cell nevus syndrome
Loss-of-function mutations of PTCH1 are the cause of basal
cell nevus syndrome, the clinical features of which were originally identified
by Dr. Robert Gorlin. This autosomal dominant disorder is distinguished by the development of benign and malignant tumors, including
multiple BCCs, medulloblastomas and ovarian fibromas, and less frequently fibrosarcomas, meningiomas, rhabdomyosarcomas and cardiac fibromas. The disorder is also characterized by
developmental defects such as pits of the palms and soles, keratocysts of the jaw and other dental malformations, cleft palate, calcification of the falx cerebri, spina bifida occulta and other spine anomalies, and bifid ribs and other rib anomalies [62–64]. Analysis of the distribution of BCCs in affected individuals in
multiple families suggests that the underlying defect might be a
mutation in a tumor suppressor gene. This gene was later mapped to chromosome
9q22-31, which is also frequently deleted in sporadic BCCs [65]. Positional cloning and candidate gene approaches identified the
human homolog of Drosophila patched as a candidate gene for therapeutic strategies [59,60,66]. Making PTCH1
a good candidate gene for basal cell nevus syndrome, vertebrate patched
was known to function in the development of organs, such as neural tube, somites and limb buds [67], with abnormalities. Screening of the patched
coding region in basal cell nevus syndrome patients revealed
a wide spectrum of mutations, the majority of which were predicted to result in
premature protein truncation. PTCH mutations are mainly clustered into
two large extracellular loops and a large intracellular loop [68]. Kindreds
with identical mutations differ dramatically in the extent of
their clinical features, suggesting that genetic background or
environmental factors may have an important role in modifying the
spectrum of both developmental and neoplastic traits [69].
The tumor suppressor role of PTCH1
has been further demonstrated in mice. Mice heterozygous for a PTCH1
null mutation exhibit the same essential features, such as tumor development (eg
medulloblastomas, rhabdomyosarcomas and BCCs) and developmental defects
(eg pina bifida occulta), as basal cell nevus syndrome patients [70,72].
The mouse studies confirm that PTCH1 functions as a tumor suppressor.
Activation of the Hh pathway in sporadic BCCs
BCC, the most common human cancer, consistently has abnormalities of
the Hh pathway and often loses PTCH1 function due to point mutations and
the loss of the remaining allele. Most PTCH1 mutations lead to loss of
the protein function. Mice heterozygous for a PTCH1 null mutation
develop BCCs following UV irradiation or ion radiation. Currently, PTCH+/– mice represent the most practical model for UV-mediated BCC
formation [72]. The PTCH1 gene region is lost in more than 50% of human
sporadic BCCs, whereas the Hh pathway is activated in almost all BCCs,
suggesting alteration of additional genes in the Hh pathway in this type of
skin cancer. Indeed, mutations of SMO are found in about 10% of sporadic BCCs
[73–77].
Unlike wild-type SMO, expression of activated SMO molecules in mouse skin
results in formation of BCC-like tumors [73]. These findings provide additional
insight into the role of the Hh pathway in human cancer. It has also been
reported that Su(Fu) is mutated in some BCCs [75]. LOH are not detected in the Su(Fu)
gene region, unlike in the PTCH1 region, in sporadic BCCs, suggesting
that Su(Fu) loss is not a major somatic change. Taking all the mutation data
into account, the underlying molecular basis for the activated Hh signaling
still remains unknown in approximately 30% of BCCs. Thus, we predict that
mutations of additional genes in the Hh pathway are yet to be discovered in
sporadic BCCs. We have shown that activated Hh signaling in BCCs leads to cell
proliferation through elevated expression of PDGFR [78], whereas
targeted inhibition of Hh signaling causes apoptosis via Fas induction [79].
Activation of Hh signaling in extracutaneous tumors
Recent studies indicate that Hh signaling is activated
in many types of extracutaneous tumors, including brain, gastrointestinal,
prostate, lung and breast cancers. Unlike with BCCs, overexpression of Hh
ligands is believed to be responsible for activating Hh signaling in some of
these tumors [80,81]. In pancreatic, esophageal and liver cancers, activation
of this pathway is found in both early tumors and metastatic cancer [82–84], suggesting that Hh signaling may be a
major trigger for carcinogenesis. In support of these findings, transgenic mice
with pancreatic-specific expression of Shh or Gli2 develop pancreatic tumors
[85,86]. In other tumors, such as gastric and prostate cancers, Hh signaling
activation is associated with cancer progression [82,87–90]. Consistent with these findings, inhibition of Hh
signaling in prostate and gastric cancer cells reduces cell invasiveness (our
unpublished observation)[88]. Recently, reports have suggested that Hh
signaling is required for the development and progression of melanoma, gliomas
and B-cell lymphomas [91,92].
Different, and sometimes contradictory results have
been reported regarding Hh signaling activation in different tumor types. There
are several reasons for this. First, it is possible that the involvement of Hh
signaling in human cancers may be context dependent, occurring in some tissues
or cell lines but not in others. Evidence suggests that Hh signaling may be
involved in maintaining cancer stem cell proliferation [93,94]. Second, tumor
heterogeneity is a major factor in the analysis of Hh target gene expression by
real-time polymerase chain reaction. For example, we identified activation of
the Hh pathway in prostate cancer more frequently from transurethral resection
of the prostate specimens than from prostatectomy specimens [88]. Third,
different standards have been used to define Hh signaling activation. Some
studies have used elevated expression of Gli1 as a read-out of Hh signaling
activation [50], whereas others have assessed expression of several Hh target
genes, such as Gli1, PTCH1, sFRP1 and HIP [82,83,85,90,95].
Similarly, though most studies have used multiple approaches, some have only
involved immunohistochemistry to detect Hh signaling activation [96].
Therefore, it is imperative to establish a unified standard for detecting Hh
signaling activation in human cancer. As the research in this area progresses,
we will gain a clearer picture about Hh signaling activation in human cancers. Table
2 provides a summary of current data on Hh signaling activation in human
cancers.
Small Molecule Modulators of Hh Signaling
Cyclopamine
Cyclopamine, a plant-derived steroidal
alkaloid, binds directly to the transmembrane helices of SMO and inhibits Hh
signaling [97]. The discovery of small molecule antagonists of SMO such as
cyclopamine has opened up exciting new prospects for molecularly targeted
therapy for and prevention of human cancers associated with Hh signaling.
Oral cyclopamine can block the growth of
UV-induced BCCs in PTCH1+/– mice by 50%, perhaps by increasing Fas-induced
apoptosis [79]. Furthermore, cyclopamine treatment in this mouse model prevents
the formation of additional microscopic BCCs, implying a potential use of
cyclopamine in BCC prevention. Cyclopamine administration reduced BCCs, but not
SCCs or fibrosarcomas, in these mice, highlighting the specificity of
cyclopamine for the Hh pathway [79]. Using murine BCC cell lines derived from
this mouse model, cyclopamine is shown to inhibit cell proliferation, possibly
through down-regulation of growth factor receptor PDGFR. Similarly, cyclopamine
is effective in reducing medulloblastoma development in PTCH1+/– mice as well as tumor growth of many
cancer cell lines in nu/nu mice [50,85,90,98,99].
Synthetic SMO antagonists
Other synthetic SMO antagonists, such as
CUR61414 from Curis/Genentech, have also been found to be effective in reducing
BCCs in PTCH1+/– mice.
Using an ex vivo model of BCC, CUR61414 caused the regression of
UV-induced basaltic lesions in punch biopsies taken from PTCH1+/– mice [100]. Since that study, a topical formulation
of this compound has been tested against sporadic BCCs in a phase I clinical
trial. However, for unknown reasons, the compound did not appear to affect Hh
target gene expression in this clinical trial. Additionally, several other
synthetic compounds differing structurally from cyclopamine have been
identified for their ability to bind directly to SMO [101,102].
Other Hh signaling modulators
A few small molecule inhibitors for Gli1
functions are identified through chemical library screening. Two such
inhibitors act in the nucleus to block Gli function, and one of them interferes
with Gli1 DNA binding in living cells [103]. Importantly, the discovered
compounds efficiently inhibited in vitro tumor cell proliferation in a
Gli-dependent manner and successfully blocked cell growth in an in vivo
xenograft model using human prostate cancer cells harboring downstream
activation of the Hh pathway [103]. The growth of these tumors can not be
inhibited by cyclopamine or its analogs, raising the possibility that these Hh
antagonists may have broad uses in cancer therapeutics. Clinical application of
these compounds, however, awaits additional preclinical studies in defined
tumor models.
Recent studies indicate that vitamin D3,
the secretion of which can be facilitated by PTCH1, can inhibit SMO signaling
through direct binding to SMO. This finding raises the possibility that BCCs
may be treated with nutritional supplements [104].
Since abnormal expression of Shh is very
common in several human cancer types, neutralizing antibodies for Shh have
demonstrated effectiveness in reducing cell proliferation in cancer cells with
activated Hh signaling [83]. Future clinical application of Shh neutralizing
antibodies will require additional preclinical studies.
In addition, several synthetic SMO agonists
are available for functional studies of Hh signaling in human cancer [101].
With appropriate optimization, it is possible that these Hh agonists may be
used to treat human conditions with reduced Hh signaling, such as
holoprosencephaly. Table 3 shows currently known small molecule
inhibitors of Hh signaling.
Summary
In summary, rapid advances in our
understanding of Hh signaling have provided great opportunities for developing
novel therapeutic strategies for human conditions with altered Hh signaling,
particularly cancer. Optimized use of Hh signaling antagonists will make these
therapies feasible. The challenges for therapeutic application of Hh signaling
inhibitors include identification of the right tumors for therapeutic
application; reliable and reproducible animal models for testing these
compounds; and optimization of drug dosages to minimize the side effects.
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