Targeting Gli transcription activation by small molecule suppresses tumor growth

Bosco-Clément, Geneviève; Zhang, Fang; Zhao, Chen; Zhou, Hai‐Meng; Li, Hui; Mikami, Iwao; Hirata, Tomomi; Yagui-Beltrán, Adam; Lui, Natalie S.; Hanh, T.; Cheng, Thomas K.; Tseng, Hsin-Hui; Choi, Helen; Fang, Li-Tai; Kim, Il-Jin; Yue, Dongsheng; Wang, Changli; Zheng, Qingfeng; Fujii, Naoaki; Mann, Michael J.; Jablons, David M.; He, Biao

doi:10.1038/onc.2013.164

Cited by 47 publications

(44 citation statements)

References 52 publications

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“…Targeting the Hh pathway either through RNA-interference knockdown of GLI1 and GLI2 or using Gli inhibitors, has been shown to induce growth inhibition and cell death in mesothelioma cells and xenograft tumors in vivo [13, 21, 22]. A promising anticancer agent GANT61, with Gli inhibitory activity, displayed potent cytotoxic activity against diverse human cancer types including MMe [13–15, 23–25].…”

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…Small molecules that block Gli function either directly or by blocking Gli interaction with co-activators have been proposed (Bosco-Clement et al, 2014; Lauth et al, 2007). As previously discussed, aPKC-ι/λ promotes BCC growth and may mediate Smo inhibitor resistance.…”

Section: Drivers Of Hh-dependent Tumors: Basal Cell Carcinoma and Medmentioning

confidence: 99%

Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy

2016

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Summary The Hedgehog (Hh) signaling pathway governs complex developmental processes, including proliferation and patterning within diverse tissues. These activities rely on a tightly-regulated transduction system that converts graded Hh input signals into specific levels of pathway activity. Uncontrolled activation of Hh signaling drives tumor initiation and maintenance. However, recent entry of pathway-specific inhibitors into the clinic reveals mixed patient responses and thus prompts further exploration of pathway activation and inhibition. In this review, we share emerging insights on regulated and oncogenic Hh signaling, supplemented with updates on the development and use of Hh pathway-targeted therapies.

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“…FN1-8, a synthetic small molecule comprising a pyrazoline structure (Figure 1), strongly reduces GLI-mediated transcriptional activity by disrupting the interaction of both GLI1 and GLI2 with TBP (TATA box-binding protein)-associated factor (TAF)9, a transcription coactivator (Figure 2). Noteworthy, FN1-8 was able to suppress the proliferation of lung cancer cells in vitro and in vivo and to inhibit the cell growth of numerous cancer cells that express high GLI levels, including prostate, pancreatic, colon cancer, and glioma [80].…”

Section: Reviewmentioning

confidence: 99%

Targeting GLI factors to inhibit the Hedgehog pathway

Infante

Alfonsi

Botta

et al. 2015

Trends in Pharmacological Sciences

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Hedgehog (Hh) signaling has emerged in recent years as an attractive target for anticancer therapy because its aberrant activation is implicated in several cancers. Major progress has been made in the development of SMOOTHENED (SMO) antagonists, although they have shown several limitations due to downstream SMO pathway activation or the occurrence of drug-resistant SMO mutations. Recently, particular interest has been elicited by the identification of molecules able to hit glioma-associated oncogene (GLI) factors, the final effectors of the Hh pathway, which provide a valid tool to overcome anti-SMO resistance. Here, we review results achieved in developing GLI antagonists, explaining their mechanisms of action and highlighting their therapeutic potential. We also underline the relevance of structural details in their discovery and optimization.

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Targeting Gli transcription activation by small molecule suppresses tumor growth

Cited by 47 publications

References 52 publications

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

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

Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy

Targeting GLI factors to inhibit the Hedgehog pathway

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