Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers

Nàger, Mireia; Sallán, Marta C.; Visa, Anna; Pushparaj, Charumathi; Santacana, Marı́a; Macià, Anna; Yeramian, Andrée; Cantı́, Carles; Herreros, Judit

doi:10.1080/15548627.2017.1423439

Cited by 75 publications

(57 citation statements)

References 55 publications

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“…Palbociclib (Selleckchem, Houston, TX, USA) was used at a final concentration of 2 or 5 μ m . Primary GBM cell cultures were isolated as previously described . We managed to establish 12 primary cultures, 10 GBM and two astrocytoma (grade II), and characterized Ccnd1, Cdk4, RB1 and IDH1 status in all of them.…”

Section: Methodsmentioning

confidence: 99%

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

Cemeli

Guasch‐Vallés

Nàger

et al. 2019

The Journal of Pathology

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Glioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after surgical resection. The cyclin D1 (Ccnd1)/Cdk4-retinoblastoma 1 (RB1) axis is frequently altered in GBM, leading to overproliferation by RB1 deletion or by Ccnd1-Cdk4 overactivation. High levels of Ccnd1-Cdk4 also promote GBM cell invasion by mechanisms that are not so well understood. The purpose of this work is to elucidate the in vivo role of cytoplasmic Ccnd1-Cdk4 activity in the dissemination of GBM. We show that Ccnd1 activates the invasion of primary human GBM cells through cytoplasmic RB1-independent mechanisms. By using GBM mouse models, we observed that evaded GBM cells showed cytoplasmic Ccnd1 colocalizing with regulators of cell invasion such as RalA and paxillin. Our genetic data strongly suggest that, in GBM cells, the Ccnd1-Cdk4 complex is acting upstream of those regulators. Accordingly, expression of Ccnd1 induces focal adhesion kinase, RalA and Rac1 activities. Finally, in vivo experiments demonstrated increased GBM dissemination after expression of membrane-targeted Ccnd1. We conclude that Ccnd1-Cdk4 activity promotes GBM dissemination through cytoplasmic and RB1-independent mechanisms. Therefore, inhibition of Ccnd1-Cdk4 activity may be useful to hinder the dissemination of recurrent GBM.

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Section: Methodsmentioning

confidence: 99%

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

Cemeli

Guasch‐Vallés

Nàger

et al. 2019

The Journal of Pathology

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“…Autophagy, including mitophagy and ciliaphagy, has been shown to modulate the development of COPD (Cloonan et al, 2014;Ahmad et al, 2015). Autophagy negatively regulates Wnt signaling by promoting Dishevelled degradation (Gao et al, 2010), whereas inhibition of Wnt/b-catenin signaling upregulates SQSTM1/p62 and sensitizes glioblastoma cells for proliferation and apoptosis to autophagy blockers (Nàger et al, 2018). Although SB216763, a selective small-molecule inhibitor of GSK3, protects against bleomycin-induced pulmonary fibrosis via activation of autophagy (Gurrieri et al, 2010), it remains elusive whether there is an interaction between autophagy and Wnt signaling during the development of COPD.…”

Section: Wnt Pathway In Copdmentioning

confidence: 99%

Perspectives on Wnt Signal Pathway in the Pathogenesis and Therapeutics of Chronic Obstructive Pulmonary Disease

Gao

et al. 2019

J Pharmacol Exp Ther

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Chronic obstructive pulmonary disease (COPD) is a chronic lung disease with progressive airflow limitation and functional decline. The pathogenic mechanisms for this disease include oxidative stress, inflammatory responses, disturbed protease/antiprotease equilibrium, apoptosis/proliferation imbalance, senescence, autophagy, metabolic reprogramming, and mitochondrial dysfunction. The Wnt signaling pathway is an evolutionarily conserved signaling pathway that is abnormal in COPD, including chronic bronchitis and pulmonary emphysema. Furthermore, Wnt signaling has been shown to modulate aforementioned cellular processes involved in COPD. From this perspective, we provide an updated understanding of the crosstalk between Wnt signal and these cellular processes, and highlight the crucial role of the Wnt signal during the development of COPD. We also discuss the potential for targeting the Wnt signal in future translational and pharmacological therapeutics aimed at prevention and treatment of this disease.

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“…CTNNB1 (β-catenin) is a key protein of Wnt signals and linked to the development of tumor (18). As reported, CTNNB1 could affect autophagy in glioblastoma, and cell autophagy was related to the tumor microenvironment (19) and was also involved in adrenocortical carcinomas (20). Molecular mechanism related in CRC was correlated with CTNNB1; for instance, genetic variations of the CTNNB1 were related to the progression of CRC (21).…”

Section: Discussionmentioning

confidence: 91%

Regulatory Mechanism of ITGBL1 in the Metastasis of Colorectal Cancer

2020

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Integrin, beta-like 1 (ITGBL1) protein is located in the extracellular matrix (ECM) and involved in the development and metastasis of many tumors. However, the regulatory mechanism of ITGBL1 in colorectal cancer (CRC) remains unclear. This study was to analyze the expression profile of CRC and to identify the expression change of ITGBL1 gene at different stages of CRC. Survival analysis showed that ITGBL1 was related to the metastasis of CRC, and CRC patients with a high expression of ITGBL1 had earlier metastasis. Gene Set Enrichment Analysis (GSEA) indicated the relationship between ITGBL1 expression and molecular events of CRC. The results indicated that a high expression of ITGBL1 was linked to Wnt signaling pathway, cell polarity, and tissue development, while a low expression of ITGBL1 was related to cellular respiration, electron transfer chain, and oxidative phosphorylation. With the expression profiles from interstitial and parenchyma CRC tissues, a comparison was made to determine the difference between high/low expression of ITGBL1 and Wnt signaling pathway, respectively, and further confirmed the close relation between ITGBL1 and Wnt signaling pathway. To determine the relation, an interaction network of ITGBL1 and Wnt signaling proteins was constructed. It was found that β-catenin interacted with multiple extracellular Wnt signals and could bind to ITGBL1. As a result, the regulatory mechanism of ITGBL1 in CRC is related to extracellular Wnt signals and may affect extracellular Wnt signals via β-catenin.

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Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers

Cited by 75 publications

References 55 publications

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

Perspectives on Wnt Signal Pathway in the Pathogenesis and Therapeutics of Chronic Obstructive Pulmonary Disease

Regulatory Mechanism of ITGBL1 in the Metastasis of Colorectal Cancer

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