Mode and specificity of binding of the small molecule GANT61 to GLI determines inhibition of GLI-DNA binding

Agyeman, Akwasi; Jha, Babal K.; Mazumdar, Tapati; Houghton, Janet A.

doi:10.18632/oncotarget.2046

Cited by 107 publications

(120 citation statements)

References 71 publications

(124 reference statements)

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“…However, cyclopamine were not so effective for various cancer types in which Hedgehog ligand over-expression is considered to drive caner growth [48]. A small molecule inhibitor of Gli1 and Gli2, GANT61, was recently identified, acts in the nucleus to blocked Gli1-DNA binding and shows a high specificity for Hedgehog signaling [49]. Based on the above notions, in this study, we applied hBMSC-exosomes to treated different cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Promote Tumor Growth Through Hedgehog Signaling Pathway

Qi¹,

Zhou²,

Zhang³

et al. 2017

Cell Physiol Biochem

156

103

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Background/Aims: Mesenchymal stem/stromal cells (MSCs) are known to home to sites of tumor microenvironments where they participate in the formation of the tumor microenvironment and to interplay with tumor cells. However, the potential functional effects of MSCs on tumor cell growth are controversial. Here, we, from the view of bone marrow MSC-derived exosomes, study the molecular mechanism of MSCs on the growth of human osteosarcoma and human gastric cancer cells. Methods: MSCs derived from human bone marrow (hBMSCs) were isolated and cultured in complete DMEM/F12 supplemented with 10% exosome-depleted fetal bovine serum and 1% penicillin-streptomycin, cell culture supernatants containing exosomes were harvested and exosome purification was performed by ultracentrifugation. Osteosarcoma (MG63) and gastric cancer (SGC7901) cells, respectively, were treated with hBMSC-derived exosomes in the presence or absence of a small molecule inhibitor of Hedgehog pathway. Cell viability was measured by transwell invasion assay, scratch migration assay and CCK-8 test. The expression of the signaling molecules Smoothened, Patched-1, Gli1 and the ligand Shh were tested by western blot and RT-PCR. Results: In this study, we found that hBMSC-derived exosomes promoted MG63 and SGC7901 cell growth through the activation of Hedgehog signaling pathway. Inhibition of Hedgehog signaling pathway significantly suppressed the process of hBMSC-derived exosomes on tumor growth. Conclusion: Our findings demonstrated the new roles of hedgehog signaling pathway in the hBMSCs-derived exosomes induced tumor progression.

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Section: Discussionmentioning

confidence: 99%

Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Promote Tumor Growth Through Hedgehog Signaling Pathway

Qi¹,

Zhou²,

Zhang³

et al. 2017

Cell Physiol Biochem

156

103

View full text Add to dashboard Cite

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“…Notably, several studies observed superior anticancer efficacy of GANT61 compared with Smo inhibitors cyclopamine or GDC-0449 (30)(31)(32)(33)(34). GANT61 is a highly selective inhibitor interfering with DNA binding of both GLI1 and GLI2 without having influence on pathways such as Ras-Raf-Mek-Mapk, TNF signaling/NF-kB, or C/EBPa (27,35).…”

Section: Discussionmentioning

confidence: 99%

Expression of Hedgehog Pathway Mediator GLI Represents a Negative Prognostic Marker in Human Acute Myeloid Leukemia and Its Inhibition Exerts Antileukemic Effects

Wellbrock

Latuske

Köhler

et al. 2015

Clinical Cancer Research

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Purpose: The Hedgehog pathway plays an important role in stem-cell biology and malignant transformation. Therefore, we investigated the expression and prognostic impact of Hedgehog pathway members in acute myeloid leukemia (AML).Experimental Design: Pretreatment samples from 104 newly diagnosed AML patients (AMLSG 07-04 trial) were analyzed by qPCR, and expression of Hedgehog family members was correlated with clinical outcome. Inhibition of GLI by GANT61 or shRNA was investigated in AML cells in vitro and in vivo.Results: Expression of receptors Smoothened and Patched-1 and their downstream mediators, GLI1, GLI2, and GLI3, was found in AML patients in contrast to Hedgehog ligands. GLI2 expression had a significant negative influence on event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS; P ¼ 0.037, 0.026, and 0.013, respectively) and was correlated with FLT3 mutational status (P < 0.001). Analysis of a second, independent patient cohort confirmed the negative impact of GLI2 on EFS and OS (P ¼ 0.007 and 0.003, respectively; n ¼ 290). Within this cohort, GLI1 had a negative prognostic impact (P < 0.001 for both EFS and OS). Although AML cells did not express Hedgehog ligands by qPCR, AML patients had significantly increased Desert Hedgehog (DHH) plasma levels compared with healthy subjects (P ¼ 0.002), in whom DHH was presumably provided by bone marrow niche cells. Moreover, the GLI inhibitor GANT61 or knockdown of GLI1/2 by shRNA caused antileukemic effects, including induction of apoptosis, reduced proliferation, and colony formation in AML cells, and a survival benefit in mice.Conclusions: GLI expression is a negative prognostic factor and might represent a novel druggable target in AML. Clin Cancer Res; 21(10); 2388-98. Ó2015 AACR.

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“…A promising anticancer agent GANT61, with Gli inhibitory activity, displayed potent cytotoxic activity against diverse human cancer types including MMe [13–15, 23–25]. On the basis of computational docking and surface plasmon resonance data, GANT61 has been proposed to mediate its pro-apoptotic effect by binding directly to GLI1, which in turn inhibits GLI1 from binding to DNA [9, 26]. There is evidence that GANT61 appears to have a novel anticancer mechanism that differs from other Hh antagonists.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis

et al. 2015

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Gli transcription factors of the Hedgehog (Hh) pathway have been reported to be drivers of malignant mesothelioma (MMe) cell survival. The Gli inhibitor GANT61 induces apoptosis in various cancer cell models, and has been associated directly with Gli inhibition. However various chemotherapeutics can induce cell death through generation of reactive oxygen species (ROS) but whether ROS mediates GANT61-induced apoptosis is unknown. In this study human MMe cells were treated with GANT61 and the mechanisms regulating cell death investigated. Exposure of MMe cells to GANT61 led to G1 phase arrest and apoptosis, which involved ROS but not its purported targets, GLI1 or GLI2. GANT61 triggered ROS generation and quenching of ROS protected MMe cells from GANT61-induced apoptosis. Furthermore, we demonstrated that mitochondria are important in mediating GANT61 effects: (1) ROS production and apoptosis were blocked by mitochondrial inhibitor rotenone; (2) GANT61 promoted superoxide formation in mitochondria; and (3) mitochondrial DNA-deficient LO68 cells failed to induce superoxide, and were more resistant to apoptosis induced by GANT61 than wild-type cells. Our data demonstrate for the first time that GANT61 induces apoptosis by promoting mitochondrial superoxide generation independent of Gli inhibition, and highlights the therapeutic potential of mitochondrial ROS-mediated anticancer drugs in MMe.

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Mode and specificity of binding of the small molecule GANT61 to GLI determines inhibition of GLI-DNA binding

Cited by 107 publications

References 71 publications

Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Promote Tumor Growth Through Hedgehog Signaling Pathway

Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Promote Tumor Growth Through Hedgehog Signaling Pathway

Expression of Hedgehog Pathway Mediator GLI Represents a Negative Prognostic Marker in Human Acute Myeloid Leukemia and Its Inhibition Exerts Antileukemic Effects

Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis

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