Gli1 is a potential target for alleviating multidrug resistance of gliomas

Cui, Daming; Xu, Qiwu; Wang, Ke; Che, Xiaoming

doi:10.1016/j.jns.2009.09.006

Cited by 68 publications

(62 citation statements)

References 38 publications

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“…TGF␤), can act as both a positive and negative regulator of tumor development (8, 10, 11, 29, 44 -47). Examination of human and mouse tumor samples by immunohistochemistry or global arrays (49,(52)(53)(54)(55) demonstrates that the expression of GLI1 in many cancers often correlates with poor prognosis. Therefore, GLI1 expression signatures are often associated with cancer progression and metastasis (50,51).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of the Transcription Factor GLI1 Accelerates Pancreatic Cancer Progression

Mills

Zhang²,

Marler

et al. 2014

Journal of Biological Chemistry

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Background: GLI1 is required for pancreatic tumor initiation; however, its role at later stages of carcinogenesis remains elusive. Results: Genetic inactivation of GLI1 accelerates pancreatic cancer progression. Conclusion: GLI1 can act as both a promoter and suppressor of pancreatic carcinogenesis depending on the tumor stage. Significance: This knowledge increases our understanding of pancreatic carcinogenesis and may help the design of therapies targeting GLI1-related pathways.

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Section: Discussionmentioning

confidence: 99%

Inactivation of the Transcription Factor GLI1 Accelerates Pancreatic Cancer Progression

Mills

Zhang²,

Marler

et al. 2014

Journal of Biological Chemistry

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“…43 GLI1 has frequently been implicated in cancer cell therapy resistance through decreased chemotherapy and radiotherapy responsiveness [44][45][46][47][48] and increased expression of cell surface drug transporters. [49][50][51] Recently, GLI1 was shown to drive resistance of AML cells to ribavirin and cytarabine through UGT1A-dependent glucuronidation of the compounds and inhibition of GLI1 with GANT61 restored sensitivity. 52 Additionally, SMO-independent GLI1 activity is important for adjusted p value < 0.05 adjusted p value ≥ 0.05 osteopontin-mediated resistance of breast cancer cells to the cytotoxic effects of doxorubicin, paclitaxel and cisplatin.…”

Section: Discussionmentioning

confidence: 99%

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

et al. 2016

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Vorinostat is an FDA-approved histone deacetylase inhibitor (HDACi) that has proven clinical success in some patients; however, it remains unclear why certain patients remain unresponsive to this agent and other HDACis. Constitutive STAT (signal transducer and activator of transcription) activation, overexpression of prosurvival Bcl-2 proteins and loss of HR23B have been identified as potential biomarkers of HDACi resistance; however, none have yet been used to aid the clinical utility of HDACi. Herein, we aimed to further elucidate vorinostat-resistance mechanisms through a functional genomics screen to identify novel genes that when knocked down by RNA interference (RNAi) sensitized cells to vorinostat-induced apoptosis. A synthetic lethal functional screen using a whole-genome protein-coding RNAi library was used to identify genes that when knocked down cooperated with vorinostat to induce tumor cell apoptosis in otherwise resistant cells. Through iterative screening, we identified 10 vorinostatresistance candidate genes that sensitized specifically to vorinostat. One of these vorinostat-resistance genes was GLI1, an oncogene not previously known to regulate the activity of HDACi. Treatment of vorinostat-resistant cells with the GLI1 smallmolecule inhibitor, GANT61, phenocopied the effect of GLI1 knockdown. The mechanism by which GLI1 loss of function sensitized tumor cells to vorinostat-induced apoptosis is at least in part through interactions with vorinostat to alter gene expression in a manner that favored apoptosis. Upon GLI1 knockdown and vorinostat treatment, BCL2L1 expression was repressed and overexpression of BCL2L1 inhibited GLI1-knockdown-mediated vorinostat sensitization. Taken together, we present the identification and characterization of GLI1 as a new HDACi resistance gene, providing a strong rationale for development of GLI1 inhibitors for clinical use in combination with HDACi therapy.

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“…По некоторым данным, активации этого сигнального пути происходит при рецидивирующих глиобластомах [51]. Например, гиперэкспрессия GLI1 отмечается при рецидивах, возникающих после курса химиотерапии [53].…”

Section: изменения сигнального пути Hedgehog при глиомахunclassified

“…Предполагается, что путём паракринной регуляции молекулами Shh клетки периопухолевого пространства влияют на активность сигнального пути в опухолевых клетках [3,57]. Есть версии, что кроме эндотелиоцитов и астроцитов периопухолевого пространства источником лиганда Shh в опухоли могут быть нейрональные и неопластические клетки [50,51,53,57,60,63]. При этом в остальных клетках глиомы Shh отсутствует или его количество снижено [64].…”

Section: изменения сигнального пути Hedgehog при глиомахunclassified

“…Сигнальный путь HH через транскрипционный фактор GLI1 способен влиять на экспрессию генов ABC переносчиков ABCG2, MDR1, MRP1 и генов MVP и MGMT, принимающих участие в формировании химиорезистентности [53,90,91]. Показано, что GLI1 влияет на экспрессию MGMT, связываясь с GLI1-связывающим сайтом в его промотере [92].…”

Section: влияние на процессы химиорезистентностиunclassified

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Hedgehog signaling in the pathogenesis of neuro-oncology diseases

et al. 2015

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The review summarizes current knowledge on the Hedgehog signaling pathway, its role in normal embryogenesis and/or initiation and progression of neuro-oncological diseases, especially of high-grade gliomas, the most malignant neuroepithelial tumors. The main proteins forming the Hedgehog signaling pathway include Shh, PTCH1, SMO, HHIP, SUFU and GLI1 isoforms. Effects of other signaling pathways on the family of transcription factors GLI and other proteins are described. The review summarizes modern data about the impact of the Hedgehog signaling pathway on proliferation, migration activity and invasiveness, and also on tumor neoangiogenesis and tumor cell chemoresistance. The role of the Hedgehog signaling pathway in origin of cancer stem cells and epithelial-mesenchymal transition is also analyzed. Some prospects for new anticancer drugs acting on components of the Hedgehog signaling pathway inhibitors are demonstrated.

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Gli1 is a potential target for alleviating multidrug resistance of gliomas

Cited by 68 publications

References 38 publications

Inactivation of the Transcription Factor GLI1 Accelerates Pancreatic Cancer Progression

Inactivation of the Transcription Factor GLI1 Accelerates Pancreatic Cancer Progression

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

Hedgehog signaling in the pathogenesis of neuro-oncology diseases

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