Gli1 contributes to cellular resistance to cisplatin through altered cellular accumulation of the drug

Amable, Lauren; Fain, Jason; Gavin, Elaine; Reed, Eddie

doi:10.3892/or.2014.3257

Cited by 22 publications

(25 citation statements)

References 26 publications

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“…of proteins that is required for drug efflux (39). Amable et al showed that Gli1 plays a role in the cellular accumulation of cisplatin through the regulation of multiple transport proteins including octamer-binding protein (OCT)1, OCT2, OCT3, the copper transporter CTR1 and the ATPase copper transporter ATP7B (40). On the other hand, cisplatin, in turn, affects the Hh pathway.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Gli leads to antitumor growth and enhancement of cisplatin-induced cytotoxicity in large cell neuroendocrine carcinoma of the lung

et al. 2018

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Large cell neuroendocrine carcinoma (LCNEC) of the lung is a highly aggressive tumor without established standard treatment. The Hedgehog (Hh) signal, which is critical in embryogenesis, is known to play important roles in maintaining a malignant phenotype in various cancers. The present study explored the possibility of targeting the Hh signal in the treatment of LCNEC by suppressing Hh downstream molecules, Smoothened (Smo) and GLI family zinc finger 1/2 (Gli1/2), in 3 human LCNEC cell lines. Smo inhibitor, BMS-833923, and Gli inhibitor, GANT61, downregulated Gli1 and 2, resulting in the suppression of the cell viability of the 3 cell lines as assessed using an MTT assay. The downregulation of Gli1 and/or Gli2 using siRNA for each gene also led to cell growth inhibition in the 3 cell lines. The downregulation of Gli1/2 made the cells more sensitive to cisplatin, resulting in increased apoptosis. These findings suggest that the Hh signaling pathway may be a candidate target for the treatment of LCNEC of the lung.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Gli leads to antitumor growth and enhancement of cisplatin-induced cytotoxicity in large cell neuroendocrine carcinoma of the lung

et al. 2018

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“…GLI1 also plays a pivotal role in cellular accumulation of cisplatin in cisplatin-resistant A2780-CP70 human ovarian cancer cells (Amable et al , 2014). Pretreatment of the cisplatin-resistant human ovarian cancer cell line A2780-CP70 with anti-GLI1 shRNA resulted in supra-additive cell killing with cisplatin.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts

et al. 2016

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Background:The Hedgehog (Hh) pathway is upregulated in cervical cancer and associated with poor outcome. We explored the effects of Hh pathway inhibition in combination with RTCT in a patient derived orthotopic cervical cancer xenograft model (OCICx).Methods:5E1, a monoclonal antibody for SHH, or Sonidegib (LDE225), a clinical SMO inhibitor (Novartis) were added to RTCT. We investigated tumour growth delay, metastasis and GI toxicity using orthotopic cervical cancer xenografts models. The xenografts were treated with radiotherapy (15 × 2 Gy daily fractions over 3 weeks) and weekly cisplatin 4 mg kg−1 concurrently, with or without 5E1 or Sonidegib (LDE225). The Hh inhibitors were administered by subcutaneous injection (5E1; 20 mg kg−1 weekly for 3 weeks), or by oral gavage (Sonidegib; 60 mg kg−1 daily for 3 weeks).Results:We observed that both Hh inhibitors administered with RTCT were well tolerated and showed increased tumour growth delay, and reduced metastasis, with no increase in acute GI-toxicity relative to RTCT alone.Conclusions:Our data suggest Hh can be a valid therapeutic target in cervical cancer and supports data suggesting a potential therapeutic role for targeting Hh in patients undergoing RTCT. This warrants further investigation in clinical trials.

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“…On the other hand, in Hh driven cancers, the therapies of Gli inhibitors are often reported to be related to drug resistance (44,45). However, the underlying mechanism is unclear.…”

Section: Discussionmentioning

confidence: 99%

Nek2A/SuFu feedback loop regulates Gli-mediated Hedgehog signaling pathway

Zhou

Huang

et al. 2016

International Journal of Oncology

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Suppressor of Fused (SuFu), one of the most conserved components of the Hedgehog (Hh) signaling, binds Gli transcription factors and impedes activation of target gene expression in mammalian cells. Despite the central importance of SuFu in the Hh pathway, little is known about SuFu regulation. In a previous study, we identified NIMA-related expressed kinase 2A (Nek2A) as a SuFu-interacting protein. Here, we show that Nek2A stabilizes SuFu through impairing ubiquitin/proteasome degradation of SuFu. In addition, Nek2A negatively regulates target genes of Hh signaling as well as Gli2 transcriptional activity. In turn, inhibition of Hh signaling by GANT61 diminishes mRNA and protein levels of Nek2A, and Hh agonist promotes transcription of NEK2A gene. Chromatin immunoprecipitation assays revealed that Gli1 and Gli2 directly bind to the promoter regions of NEK2A gene and induced its transcription. Thus, we uncovered one of the mechanisms by which Nek2A acts as a modulator of the Hh signaling pathway in the context of a novel negative-feedback loop, which may offer new insights into Gli-mediated Hh signaling regulation in development and human diseases.

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Gli1 contributes to cellular resistance to cisplatin through altered cellular accumulation of the drug

Cited by 22 publications

References 26 publications

Inhibition of Gli leads to antitumor growth and enhancement of cisplatin-induced cytotoxicity in large cell neuroendocrine carcinoma of the lung

Inhibition of Gli leads to antitumor growth and enhancement of cisplatin-induced cytotoxicity in large cell neuroendocrine carcinoma of the lung

Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts

Nek2A/SuFu feedback loop regulates Gli-mediated Hedgehog signaling pathway

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