Targeting Hedgehog signaling and understanding refractory response to treatment with Hedgehog pathway inhibitors

2012 ◽  
Vol 15 (4) ◽  
pp. 211-222 ◽  
Author(s):  
Karla C.S. Queiroz ◽  
C. Arnold Spek ◽  
Maikel P. Peppelenbosch
Keyword(s):  
Hedgehog Signaling ◽  
Hedgehog Pathway ◽  
Response To Treatment

scholarly journals Hedgehog Signaling and Embryonic Craniofacial Disorders

2019 ◽  
Vol 7 (2) ◽  
pp. 9 ◽  
Author(s):  
Abramyan
Keyword(s):  
Hedgehog Signaling ◽  
Developmental Disorders ◽  
Critical Role ◽  
Hedgehog Pathway ◽  
Developmental Defects ◽  
Downstream Target ◽  
Secondary Palate ◽  
The Face ◽  
Range Of Functions ◽  
Key Aspects

Since its initial discovery in a Drosophila mutagenesis screen, the Hedgehog pathway has been revealed to be instrumental in the proper development of the vertebrate face. Vertebrates possess three hedgehog paralogs: Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). Of the three, Shh has the broadest range of functions both in the face and elsewhere in the embryo, while Ihh and Dhh play more limited roles. The Hedgehog pathway is instrumental from the period of prechordal plate formation early in the embryo, until the fusion of the lip and secondary palate, which complete the major patterning events of the face. Disruption of Hedgehog signaling results in an array of developmental disorders in the face, ranging from minor alterations in the distance between the eyes to more serious conditions such as severe clefting of the lip and palate. Despite its critical role, Hedgehog signaling seems to be disrupted through a number of mechanisms that may either be direct, as in mutation of a downstream target of the Hedgehog ligand, or indirect, such as mutation in a ciliary protein that is otherwise seemingly unrelated to the Hedgehog pathway. A number of teratogens such as alcohol, statins and steroidal alkaloids also disrupt key aspects of Hedgehog signal transduction, leading to developmental defects that are similar, if not identical, to those of Hedgehog pathway mutations. The aim of this review is to highlight the variety of roles that Hedgehog signaling plays in developmental disorders of the vertebrate face.

scholarly journals Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

2019 ◽  
Vol 30 (11) ◽  
pp. 2103-2111 ◽  
Author(s):  
Ming Ma ◽  
Emilie Legué ◽  
Xin Tian ◽  
Stefan Somlo ◽  
Karel F. Liem
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Mouse Models ◽  
Hedgehog Signaling ◽  
Autosomal Dominant ◽  
Cyst Formation ◽  
Hedgehog Pathway ◽  
Adult Onset ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

BackgroundPKD1 or PKD2, the two main causal genes for autosomal dominant polycystic kidney disease (ADPKD), encode the multipass transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins localize to the primary cilium, an organelle essential for cell signaling, including signal transduction of the Hedgehog pathway. Mutations in ciliary genes that build and maintain the cilium also cause renal cystic disease through unknown pathways. Although recent studies have found alterations in Hedgehog signaling in ADPKD-related models and tissues, the relationship between Hedgehog and polycystic kidney disease is not known.MethodsTo examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation in vivo in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of Pkd1 combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in Pkd1 initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of Pkd1, we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity.ResultsWe found that in Pkd1 conditional mutant mouse kidneys, neither downregulation nor activation of the Hedgehog pathway in epithelial cells along the nephron significantly influenced the severity of the polycystic kidney phenotype in mouse models of developmental or adult-onset of ADPKD.ConclusionsThese data suggest that loss of Pkd1 function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.

scholarly journals SMO-M2 mutation does not support cell-autonomous Hedgehog activity in cerebellar granule cell precursors

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Marialaura Petroni ◽  
Maria Sahùn Roncero ◽  
Valentina Ramponi ◽  
Francesca Fabretti ◽  
Vittoria Nicolis Di Robilant ◽  
...  
Keyword(s):  
Granule Cell ◽  
Hedgehog Signaling ◽  
Granule Cells ◽  
Culture Method ◽  
Hedgehog Pathway ◽  
Cellular Models ◽  
Autonomous Activity ◽  
Neoplastic Disorders ◽  
Granule Cell Precursors

AbstractGrowth and patterning of the cerebellum is compromised if granule cell precursors do not properly expand and migrate. During embryonic and postnatal cerebellar development, the Hedgehog pathway tightly regulates granule cell progenitors to coordinate appropriate foliation and lobule formation. Indeed, granule cells impairment or defects in the Hedgehog signaling are associated with developmental, neurodegenerative and neoplastic disorders. So far, scant and inefficient cellular models have been available to study granule cell progenitors, in vitro. Here, we validated a new culture method to grow postnatal granule cell progenitors as hedgehog-dependent neurospheres with prolonged self-renewal and ability to differentiate into granule cells, under appropriate conditions. Taking advantage of this cellular model, we provide evidence that Ptch1-KO, but not the SMO-M2 mutation, supports constitutive and cell-autonomous activity of the hedgehog pathway.

Targeting the Hedgehog Signaling Pathway in Therapy-Resistant BCR-ABL1 Positive Leukemia with Ponatinib

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 63-63
Author(s):  
Seiichiro Katagiri ◽  
Tetsuzo Tauchi ◽  
Seiichi Okabe ◽  
Eishi Ashihara ◽  
Shinya Kimura ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Kinase Inhibitor ◽  
Leukemia Cell ◽  
Hedgehog Pathway ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
Combined Effects ◽  
Human Leukemia Cell Line ◽  
Induction Of Apoptosis

Abstract Abstract 63 The hedgehog signaling pathway is a key regulator of cell growth and differentiation during development. While the hedgehog pathway is inactive in most normal adult tissues, hedgehog pathway reactivation has been implicated in the pathogenesis of several neoplasms. Recent studies demonstrated that hedgehog pathway is involved in the development of B cell acute lymphoblastic leukemia (B-ALL), as well as self-renewal and survival of B-ALL. Vismodegib is a selective hedgehog pathway inhibitor that blocks hedgehog signaling by binding to Smo and inhibiting activation of downstream hedgehog target genes. In the present study, we investigated the combined effects of vismodegib and ponatinib, a pan-ABL1 kinase inhibitor, in mutant forms of BCR-ABL1-expressing BaF3 cells and T315I-expressing human leukemia cell line, SK-9 (Exp Hematol. 2010; 38:765). We observed that the treatments with sonic hedgehog (Shh) enhanced the proliferation of SK-9 cells, correlated with the up regulation of Cyclin D2 and Bcl-2. The treatment with Shh significantly reduced the induction of apoptosis in ponatinib-treated SK-9 cells, however, co-tratment with vismodegib and ponatinib resulted in significantly more induction of apoptosis in Shh-treated SK-9 cells. Combined treatment with vismodegib and ponatinib in SK-9 cells also associated with the reduction of Cyclin D2 and Bcl-2, and more PARP cleavage, resulting from increased activation of caspase-3 and -9 during apoptosis. We next conducted the experiments to further evaluate the mechanism of cooperation between vismodegib and ponatinib in SK-9 cells. SK-9 cells were transfected with control siRNA or Smo siRNA or Gli1 siRNA. At 48 h after transfection, Shh co-cultured SK-9 cells were treated with indicated concentration of ponatinib for 48 h, and viable cells were counted. In the presence of Smo siRNA or Gli1 siRNA, SK-9 cells increased antiproliferative activity with ponatinib. These results demonstrated that hedgehog signaling activation impairs the efficacy of pan-ABL1 kinase inhibitor. To assess the in vivo efficacy of ponatinib and vismodegib, athymic nude mice were injected s.c. with BaF3 cells expressing wild-type (WT)-BCR-ABL1 and BCR-ABL1 mutants (M244V, G250E, Q252H, Y253F, E255K, T315A, T315I, F317L, F317V, M351T, H396P). 5 days after injection (average tumor volume, 100 mm3), the mice were randomized into four groups (5 mice per group), with each group receiving either vehicle, ponatinib (30 mg/kg; q.d.), vismodegib (10 mg/kg; q.d.), ponatinib (30 mg/kg; q.d.) + vismodegib (10 mg/kg; q.d.). The ponatinib and vismodegib combination more effectively inhibited tumor growth in mice compared to either vehicle- or ponatinib- or vismodegib-treated mice. Histopathologic analysis of tumor tissue from ponatinib + vismodegib-treated mice demonstrated an increased number of apoptotic cells detected by TUNEL stain. To investigate combined effects of vismodegib and ponatinib on T315I-expressing human leukemia cell line, NOD/SCID mice were injected intravenously with SK-9 cells. Treatment with vismodegib and ponatinib demonstrated a marked segregation of apoptotic cells in both the central bone-marrow cavity, the endosteal surface, spleen and liver. These results suggest that the combination with a Smo inhibitor and ABL1 tyrosine kinase inhibitors (TKIs) may help to eliminate the therapy-resistant T315I BCR-ABL1 positive ALL cells. In summary, our preclinical results indicate that vismodegib has potential as an important option for controlling minimal residual cells in BCR-ABL1-positive ALL. The combined results of cell-based, and in vivo studies suggest that vismodegib exhibits sufficient activity against mutants form of BCR-ABL1 to warrant consideration for combined use with pan-ABL1 TKIs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The presynaptic glycine transporter GlyT2 is regulated by the Hedgehog pathway in vitro and in vivo

2020 ◽  
Author(s):  
A. de la Rocha-Muñoz ◽  
E. Núñez ◽  
S. Gómez-López ◽  
B. López-Corcuera ◽  
J. de Juan-Sanz ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Hedgehog Pathway ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Transport Activity ◽  
Spinal Cord Neurons ◽  
Glycine Transporter ◽  
Glycinergic Neurotransmission

ABSTRACTThe identity of a glycinergic synapse is maintained presynaptically by the activity of a surface glycine transporter, GlyT2, which recaptures glycine back to presynaptic terminals to preserve vesicular glycine content. GlyT2 loss-of-function mutations cause Hyperekplexia, a rare neurological disease in which loss of glycinergic neurotransmission causes generalized stiffness and strong motor alterations. However, the molecular underpinnings controlling GlyT2 activity remain poorly understood. In this work, we identify the Hedgehog pathway as a robust controller of GlyT2 expression and transport activity. Modulating the activation state of the Hedgehog pathway in vitro in rodent primary spinal cord neurons or in vivo in zebrafish embryos induced a selective control in GlyT2 expression, regulating GlyT2 transport activity. Our results indicate that activation of Hedgehog reduces GlyT2 expression by decreasing its mRNA levels and increasing its ubiquitination and degradation. This work describes a new molecular link between the Hedgehog signaling pathway and presynaptic glycine availability.

scholarly journals The Role of the Hedgehog Pathway in Chemoresistance of Gastrointestinal Cancers

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2030
Author(s):  
Yabing Liang ◽  
Ling Yang ◽  
Jingwu Xie
Keyword(s):  
Drug Resistance ◽  
Stem Cell ◽  
Cancer Therapy ◽  
Hedgehog Signaling ◽  
Hedgehog Pathway ◽  
The Novel ◽  
Gastrointestinal Cancers ◽  
Stem Cell Regulation ◽  
Novel Drugs

The hedgehog pathway, which plays a significant role in embryonic development and stem cell regulation, is activated in gastrointestinal cancers. Chemotherapy is widely used in cancer treatment. However, chemoresistance becomes a substantial obstacle in cancer therapy. This review focuses on the recent advances in the hedgehog pathway’s roles in drug resistance of gastrointestinal cancers and the novel drugs and strategies targeting hedgehog signaling.

Hedgehog Pathway Is Deregulated In Myelodysplastic Syndrome Progenitor Bone Marrow Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1533-1533 ◽  
Author(s):  
Juliana M. Xavier ◽  
Adriana Silva Santos Duarte ◽  
Fernando V Pericole ◽  
Paulo Latuf-Filho ◽  
Fabiola Traina ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Hedgehog Signaling ◽  
Bone Marrow Cells ◽  
Low Risk ◽  
Hedgehog Pathway ◽  
Shh Pathway ◽  
Healthy Donors ◽  
Cd34 Cells ◽  
Total Bone Marrow

Abstract The sonic hedgehog (Shh) pathway is a regulatory network involved in the development of cancer. The Hh ligands (Sonic Hh, Indian Hh, and Desert Hh) bind to the receptors Patched1 and Patched2, resulting in the inhibition of their repression on Smoothened (Smo). Smo is a seven-transmembrane protein, which inhibits Suppressor of Fused (SUFU), resulting in the stabilization and activation of the Gli family of transcription factors, followed by a transcriptional response to the “canonical Hh signaling”. SUFU is a negative regulator of the Hedgehog signaling pathway, through the restriction of Gli activity through cytoplasmic sequestration. Germline mutations in SUFU are involved in medulloblastoma. Dysregulation of Shh signaling has been reported to be involved in several malignancies, including chronic myeloid leukemia. To our knowledge, however, only one study has been carried out in myelodysplastic syndrome (MDS) and acute leukemia so far, and the role of this pathway in leukemogenesis is still unknown. Recently we showed an increased protein expression of Sonic and Dessert Hedgehog in addition to increased mRNA levels of PTCH and SMO in MDS bone marrow. Here, we investigated whether this increase was capable of activating Hedgehog pathway in total and in progenitor bone marrow cells. Bone marrow (BM) samples were collected from 39 MDS (25 low-risk, 14 high-risk, according WHO 2008) patients and 26 healthy donors. CD34+ cells were isolated from peripheral blood of 9 healthy donors and 20 (12 low-risk and 8 high risk) MDS patients. Relative expressions of PTCH, SMO, SUFU and GLI1 were obtained by Real time-PCR. Increased expression observed in ligands and receptors were not sufficient to upregulate the activity of Hedgehog pathway in MDS total bone marrow. The downstream effector GLI1 was under expressed in the disease as median [min-max] as follows: healthy donors 1.04[0.02-4.01]; low risk MDS 0.21[0.03-2.26]; high risk MDS 0.07[0.03-1.48] healthy donors vs low risk p=0.007; healthy donors vs high risk p=0.006. Furthermore, SUFU expression was similar in healthy donors 3.3[0.35-7.84] and in myelodysplastic (low risk 3.76[0.75-13, 2] and high risk 1.8[0.58-16.4]) bone marrows. Different from total bone marrow, the receptors Patched and SMO showed decreased expression in MDS CD34+ cells: Patched healthy donors 2.24[0.74-4.36]; low risk 0.6[0.1-3.34]; high risk 0.98[0.29-1.22] and SMO healthy donors 1.18[0.62-2.16]; low risk 0.79[0,11-1.87]; high risk 0.86[0.37-1.02]; healthy donors vs high risk MDS p=0.049. SUFU was overexpressed (healthy donors 1.44[0.75-2.39]; low risk 2.77[0.93-4.11]; high risk 1.68[1.07-3.43]; healthy donors vs low risk MDS p=.005). However, myelodysplastic progenitors had GLI1 overexpression (healthy donors 1.09[0.6-2.91]; low risk 2.93[0.75-14.52]; high risk 1.32[0.71-2.58]; healthy donors vs low risk p=0.03), indicating an activation of the Shh pathway in MDS progenitors. Recently, Kobune et al (Blood Cancer J. 2012 Sep 7) showed activation of Hedgehog signaling in primary CD34+ blasts from acute myeloid leukemia and MDS, as those cells expressed IHh, PTCH, SMO, GLI1 and GLI. Taken together, these results and ours led us to conclude that the Hedgehog pathway is activated in MDS. Since Shh pathway is being explored as a new opportunity for targeted therapies against tumors, our study suggests that the inhibition of this pathway could be strategic in the control of leukemic stem cell and MDS treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Endocannabinoids are conserved inhibitors of the Hedgehog pathway

2015 ◽  
Vol 112 (11) ◽  
pp. 3415-3420 ◽  
Author(s):  
Helena Khaliullina ◽  
Mesut Bilgin ◽  
Julio L. Sampaio ◽  
Andrej Shevchenko ◽  
Suzanne Eaton
Keyword(s):  
Mass Spectrometry ◽  
Hedgehog Signaling ◽  
Transmembrane Protein ◽  
Hedgehog Pathway ◽  
Tissue Development ◽  
Control Tissue ◽  
Lipid Mass ◽  
Biochemical Fractionation

Hedgehog ligands control tissue development and homeostasis by alleviating repression of Smoothened, a seven-pass transmembrane protein. The Hedgehog receptor, Patched, is thought to regulate the availability of small lipophilic Smoothened repressors whose identity is unknown. Lipoproteins contain lipids required to repress Smoothened signaling in vivo. Here, using biochemical fractionation and lipid mass spectrometry, we identify these repressors as endocannabinoids. Endocannabinoids circulate in human and Drosophila lipoproteins and act directly on Smoothened at physiological concentrations to repress signaling in Drosophila and mammalian assays. Phytocannabinoids are also potent Smo inhibitors. These findings link organismal metabolism to local Hedgehog signaling and suggest previously unsuspected mechanisms for the physiological activities of cannabinoids.

scholarly journals Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Claudia Pisanu ◽  
Michael J. Williams ◽  
Diana M. Ciuculete ◽  
Gaia Olivo ◽  
Maria Del Zompo ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Hedgehog Signaling ◽  
Meta Analysis ◽  
Neuronal Cell ◽  
Hedgehog Pathway ◽  
Functional Enrichment ◽  
Neuronal Cell Body ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Multiple Testing Correction

AbstractPatients with bipolar disorder (BD) show higher frequency of obesity and type 2 diabetes (T2D), but the underlying genetic determinants and molecular pathways are not well studied. Using large publicly available datasets, we (1) conducted a gene-based analysis using MAGMA to identify genes associated with BD and body mass index (BMI) or T2D and investigated their functional enrichment; and (2) performed two meta-analyses between BD and BMI, as well as BD and T2D using Metasoft. Target druggability was assessed using the Drug Gene Interaction Database (DGIdb). We identified 518 and 390 genes significantly associated with BD and BMI or BD and T2D, respectively. A total of 52 and 12 genes, respectively, were significant after multiple testing correction. Pathway analyses conducted on nominally significant targets showed that genes associated with BD and BMI were enriched for the Neuronal cell body Gene Ontology (GO) term (p = 1.0E−04; false discovery rate (FDR) = 0.025) and different pathways, including the Signaling by Hedgehog pathway (p = 4.8E−05, FDR = 0.02), while genes associated with BD and T2D showed no specific enrichment. The meta-analysis between BD and BMI identified 64 relevant single nucleotide polymorphisms (SNPs). While the majority of these were located in intergenic regions or in a locus on chromosome 16 near and in the NPIPL1 and SH2B1 genes (best SNP: rs4788101, p = 2.1E−24), five were located in the ETV5 gene (best SNP: rs1516725, p = 1E−24), which was previously associated with both BD and obesity, and one in the RPGRIP1L gene (rs1477199, p = 5.7E−09), which was also included in the Signaling by Hedgehog pathway. The meta-analysis between BD and T2D identified six significant SNPs, three of which were located in ALAS1 (best SNP: rs352165, p = 3.4E−08). Thirteen SNPs associated with BD and BMI, and one with BD and T2D, were located in genes which are part of the druggable genome. Our results support the hypothesis of shared genetic determinants between BD and BMI and point to genes involved in Hedgehog signaling as promising targets.

scholarly journals Constitutive GLI1 expression in chondrosarcoma is regulated by major vault protein via mTOR/S6K1 signaling cascade

2021 ◽  
Author(s):  
Wei Wang ◽  
Taiqiang Yan ◽  
Wei Guo ◽  
Jianfang Niu ◽  
Zhiqing Zhao ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Affinity Purification ◽  
Hedgehog Pathway ◽  
Signaling Cascade ◽  
Major Vault Protein ◽  
Purification Method ◽  
Gli1 Expression ◽  
Induced Apoptosis

AbstractHedgehog signaling plays a pivotal role in embryonic pattern formation and diverse aspects of the postnatal biological process. Perturbation of the hedgehog pathway and overexpression of GLI1, a downstream transcription factor in the hedgehog pathway, are highly relevant to several malignancies including chondrosarcoma (CS). We previously found that knocking down expression of GLI1 attenuates the disrupted Indian hedgehog (IHH) signal pathway and suppresses cell survival in human CS cells. However, the underlying mechanisms regulating the expression of GLI1 are still unknown. Here, we demonstrated the implication of GLI1 in SMO-independent pathways in CS cells. A GLI1 binding protein, major vault protein (MVP), was identified using the affinity purification method. MVP promoted the nuclear transport and stabilization of GLI1 by compromising the binding affinity of GLI1 with suppressor of fused homolog (SUFU) and increased GLI1 expression via mTOR/S6K1 signaling cascade. Functionally, knockdown of MVP suppressed cell growth and induced apoptosis. Simultaneous inhibition of MVP and GLI1 strongly inhibits the growth of CS in vitro and in vivo. Moreover, IHC results showed that MVP, GLI1, and P-p70S6K1 were highly expressed and positively correlated with each other in 71 human CS tissues. Overall, our findings revealed a novel regulating mechanism for HH-independent GLI1 expression and provide a rationale for combination therapy in patients with advanced CS.

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