Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer

Brechbiel, Jillian L.; Miller‐Moslin, Karen; Adjei, Alex A.

doi:10.1016/j.ctrv.2014.02.003

Cited by 146 publications

(126 citation statements)

References 108 publications

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“…Only 50% of the pituitaries of healthy subjects express GLI1, whereas GLI1 expression is clearly upregulated in adenomas. This is in line with the aberrant activation of the Hh pathway found in several cancer types (Brechbiel et al 2014). The expression of GLI1 shows great variability not just between healthy and tumor tissue but also within both groups.…”

Section: Discussionsupporting

confidence: 80%

The role of proto-oncogene GLI1 in pituitary adenoma formation and cell survival regulation

Lampichler¹,

Ferrer²,

Vila³

et al. 2015

Endocrine-Related Cancer

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The Hedgehog (Hh) pathway is an important regulator of early tissue patterning and stem cell propagation. It was found to be aberrantly activated in numerous types of human cancer and might be relevant in cancer stem cells. The identification of adult stem cells in the pituitary raised the question if tumor-initiating cells and Hh signaling are involved in pituitary adenoma formation. The present study aimed at the evaluation of Hh signaling in relation to stem cell and cell cycle markers in 30 human pituitary adenomas and in cultured murine adenoma cells. Therefore, expression levels of components of the Hh pathway, stem cell marker SOX2, cell cycle regulator tumor-protein 53 (TP53), proliferation marker Ki67 (MKI67) and superoxide dismutase 1 (SOD1) were evaluated in 30 human pituitary adenomas in comparison to control tissue. Modulation of cell function and target gene expression by the inhibition and activation of the Hh pathway were studied in murine adenoma cells. We show that transcription factor glioma-associated oncogene 1 (GLI1) is overexpressed in 87% of all pituitary adenomas. The expression of GLI1 significantly correlated with that of SOX2, TP53, MKI67 and SOD1. Inhibition of GLI1 resulted in the downregulation of the above genes and severe cell death in mouse adenoma cells. On the other hand, activation of the Hh pathway increased cell viability and target gene expression. In conclusion, our findings point toward an alternative, ligand-independent Hh pathway activation with GLI1 playing a major role in the cell survival of pituitary adenoma cells.

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Section: Discussionsupporting

confidence: 80%

The role of proto-oncogene GLI1 in pituitary adenoma formation and cell survival regulation

Lampichler¹,

Ferrer²,

Vila³

et al. 2015

Endocrine-Related Cancer

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“…Aberrant Hh activation has been demonstrated in breast, colon, and prostate cancer (10)(11)(12), and is closely associated with self-renewal, invasion and migration of cancer stem cells, promoting cancer progression (13,14). It was reported that Hh signaling might induce EMT in pancreatic cancer (9,15).…”

Section: Introductionmentioning

confidence: 99%

Casticin inhibits the epithelial-mesenchymal transition in ovarian carcinoma via the hedgehog signaling pathway

et al. 2018

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Abstract. Casticin inhibits migration, invasion and induced apoptosis in numerous cancer cells; however, the Hedgehog (Hh) signaling pathway is a key factor in the epithelial-mesenchymal transition (EMT). The present study aimed to assess whether casticin affects the expression of members of the Hh signaling pathway and EMT effectors in ovarian carcinoma. The ovarian cancer SKOV3 cell line was incubated in the presence of various concentrations of casticin or cyclopamine. Next, the expression levels of the main Hh signaling effector glioma-associated oncogene-1 (Gli-1) and EMT-associated factors [Twist-related protein 1 (Twist1), E-cadherin and N-cadherin] were determined by western blotting and reverse transcription-quantitative polymerase chain reaction. Cell proliferation and growth were assessed using MTT and soft agar assays; cell migration and invasion was evaluated using an in vitro migration assay and a transwell invasion assay, respectively. Compared with control group values, Gli-1, Twist1 and N-cadherin expression levels were reduced, whereas E-cadherin levels were increased in the casticin-and cyclopamine-treated groups. Incubation with casticin or cyclopamine resulted in markedly reduced SKOV3 cell viability, migration and invasion, in a dose-dependent manner. To the best of our knowledge, the findings of the present study indicated for first time that casticin may inhibit EMT via Hh signaling in vitro, reducing the migratory ability of ovarian cancer cells.

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“…Another interesting approach in the treatment of advanced GBC is the recent preclinical evidence of crosstalk between hedgehog and other signaling pathways in many other tumor types and the inhibitor combination therapy to improve the therapeutic efficacy [120]. Here we have described 4 pathways -Notch, EGFR, PI3K/ AKT/mTOR and MAPK/ERK -that are targets of the agents currently in clinical use and that have been reported to crosstalk with the recently described dysregulated hedgehog pathway in GBC.…”

Section: Multiple Intracellular Pathways Inhibition As a Translationamentioning

confidence: 90%

“…It is activated by a variety of growth signals, including EGF, PDGF, and cytokines, leading ultimately to MEK1 and MEK2 phosphorylation, and the subsequent phosphorylation and nuclear localization of ERK1 and ERK2 [120].…”

Section: Mapk/erk Signaling Pathwaymentioning

confidence: 99%

Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy

Bizama

García

Espinoza

et al. 2015

Cancer Treatment Reviews

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Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer

Cited by 146 publications

References 108 publications

The role of proto-oncogene GLI1 in pituitary adenoma formation and cell survival regulation

The role of proto-oncogene GLI1 in pituitary adenoma formation and cell survival regulation

Casticin inhibits the epithelial-mesenchymal transition in ovarian carcinoma via the hedgehog signaling pathway

Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy

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