The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

Crespo, S.; Kind, Marcus; Arcaro, Alexandre

doi:10.20517/2394-4722.2015.72

Cited by 48 publications

(38 citation statements)

References 126 publications

(142 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results also showed that the enhanced expression of LOX downstream of the PI3K-Akt-HIF-1α signaling was necessary for migration and invasion of cancer cells carrying the activated ras genes. It is well recognized that the PI3K-Akt signaling plays critical roles in metastasis of cancer cells by promoting cellular events such as invasion, migration and epithelial-mesenchymal transition (EMT) via activation of the transcription factors, Twist and Snail, and inhibition of GSK-3β [30][31][32]. Our results implied that LOX also plays a critical role in metastasis working in parallel with these known PI3K-Akt target proteins.…”

Section: Discussionsupporting

confidence: 55%

Ras inhibitors display an anti-metastatic effect by downregulation of lysyl oxidase through inhibition of the Ras-PI3K-Akt-HIF-1α pathway

et al. 2017

View full text Add to dashboard Cite

Metastasis stands as the major obstacle for the survival from cancers. Nonetheless most existing anti-cancer drugs inhibit only cell proliferation, and discovery of agents having both anti-proliferative and anti-metastatic properties would be more beneficial. We previously reported the discovery of small-molecule Ras inhibitors, represented by Kobe0065, that displayed anti-proliferative activity on xenografts of human colorectal cancer (CRC) cell line SW480 carrying the K-rasgene. Here we show that treatment of cancer cells carrying the activated ras genes with Kobe0065 or a siRNA targeting Ras downregulates the expression of lysyl oxidase (LOX), which has been implicated in metastasis. LOX expression is enhanced by co-expression of Ras through activation of phosphatidylinositol 3-kinase (PI3K)/Akt and concomitant accumulation of hypoxia-inducible factor (HIF)-1α. Furthermore, Kobe0065 effectively inhibits not only migration and invasion of cancer cells carrying the activated ras genes but also lung metastasis of human CRC cell line SW620 carrying the K-ras gene. Collectively, these results indicate that Kobe0065 prevents metastasis through inhibition of the Ras-PI3K-Akt-HIF-1α-LOX signaling and suggest that Ras inhibitors in general might exhibit both anti-proliferative and anti-metastatic properties toward cancer cells carrying the activated ras genes.

show abstract

Section: Discussionsupporting

confidence: 55%

Ras inhibitors display an anti-metastatic effect by downregulation of lysyl oxidase through inhibition of the Ras-PI3K-Akt-HIF-1α pathway

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Although the loss of CDKN2A/2B genes can be detected in samples with tumor contents <35% (a threshold set at the fold change cutoff of 0.65 for copy number loss), there is the possibility that no detection in primary NSCLC was due to the lower tumor content in comparison with BMs in 2 cases (P4 and Cancer October 15, 2019 P25). 30 Therefore, components of the PI3K signaling pathway are considered potential drug targets to inhibit the often fatal events of metastasis and cell invasion. Previous studies have reported that the amplification of CDK genes is important for functional inactivation of CDKs/RB regulatory complexes in aggressive cancers of the central nervous system, including medulloblastomas and glioblastomas.…”

Section: Discussionmentioning

confidence: 99%

“…28 It has also been reported that the PI3K pathway controls key functions necessary for cell invasion and metastasis, including cell motility, 29 and is frequently activated in the most common central nervous system cancers of adults and children, such as malignant gliomas and medulloblastomas. 30 Therefore, components of the PI3K signaling pathway are considered potential drug targets to inhibit the often fatal events of metastasis and cell invasion. However, the performance of kinase inhibitors in clinical trials has been poor thus far because of small sample sizes.…”

Section: Discussionmentioning

confidence: 99%

Genes associated with increased brain metastasis risk in non–small cell lung cancer: Comprehensive genomic profiling of 61 resected brain metastases versus primary non–small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036)

Wang

Ou²,

et al. 2019

Cancer

View full text Add to dashboard Cite

BACKGROUND: Patients with brain metastases (BMs) have a poor prognosis and limited therapeutic options. Lung cancer is the most common primary malignancy giving rise to BMs; thus, understanding the molecular mechanisms behind increased BM risk is essential for identifying therapeutic targets and developing effective interventions. METHODS: Sixty-one patients who underwent surgical resection of primary non-small cell lung cancer (NSCLC) and BMs were retrospectively studied. Comprehensive genomic profiling of primary NSCLC and matched BMs was performed with next-generation sequencing targeting 416 cancer-relevant genes. RESULTS: Mutations of major drivers, including EGFR, KRAS, TP53, and ALK, were highly concordant between primary NSCLC and matched BMs (>80%), whereas discordance suggested the unique genomic evolution and oncogenic mechanisms of NSCLC BMs. BMs also demonstrated higher levels of copy number variations in comparison with primary NSCLC. Furthermore, the alterations of genes encoding CDK4/CCND1, CDKN2A/2B, and PI3K signaling pathways were enriched in BMs, and this suggested their correlation with increased metastatic risk. Indeed, patients with activated PI3K signaling in their primary NSCLC had significantly shorter BM-free survival (hazard ratio, 8.49; P = .0005). In addition, mutated TP53 or an activated WNT pathway via CTNNB1, APC, and AXIN2 mutations trended toward shorter BM-free intervals but not significantly so. CONCLUSIONS: These findings yield detailed insights into the genomic complexity and heterogeneity of primary NSCLC and matched BMs. This study highlights the significant correlation of PI3K signaling with increased metastatic risk in patients with NSCLC and identifies genomic alterations enriched in NSCLC BMs that could serve as prognostic markers and potential therapeutic targets for treating patients with NSCLC BMs. Cancer 2019;125:3535-3544.

show abstract

“…Whether Snail is also involved needs to be explored in future research. Increasing evidence indicates that the PLC, ERK, p38, and β‐catenin signaling pathways are mediated in melatonin‐associated control of cellular effects . Stimulation of PLC, ERK, p38, and β‐catenin activators confirm that these signaling pathways regulate melatonin‐induced reductions in lung cancer stemness.…”

Section: Discussionmentioning

confidence: 96%

“…In this study, outcomes of the sphere formation assay showed that melatonin inhibits lung cancer stemness. Increasing reports suggest that the phospholipase C (PLC), ERK, p38, and Wnt/β‐catenin signaling pathways mediate melatonin‐regulated cell functions . In addition, Twist has been documented as being a critical epithelial‐mesenchymal transition (EMT) and cancer stemness regulator .…”

Section: Introductionmentioning

confidence: 99%

Melatonin reduces lung cancer stemness through inhibiting of PLC, ERK, p38, β‐catenin, and Twist pathways

Yang

Chiou

Chen³

et al. 2018

Environmental Toxicology

View full text Add to dashboard Cite

Lung cancer is one of the most common cancer in cancer-related deaths worldwide, which is characterized by its strong metastatic potential. The melatonin hormone secreted by the pineal grand has an antioxidant effect and protects cells against carcinogenic substances. However, the effects of melatonin in lung cancer stemness are largely unknown. We found that melatonin reduces CD133 expression by~50% in lung cancer cell lines, while results of a sphere formation assay showed that melatonin inhibits lung cancer stemness. These effects of melatonin were reversed when the cell lines were incubated with phospholipase C (PLC), ERK/p38, and a β-catenin activator. Transfection with Twist siRNA augmented the inhibitory effects of melatonin, indicating that melatonin suppresses lung cancer stemness by inhibiting the PLC, ERK/p38, β-catenin, and Twist signaling pathways. We also found CD133 expression is positively correlated with Twist expression in lung cancer specimens. Melatonin shows promise in the treatment of lung cancer stemness and deserves further study. K E Y W O R D S lung cancer, melatonin, stemness, Twist 1 | INTRODUCTION Lung cancer is a major occasion of cancer mortality. Non-small cell lung cancer (NSCLC) is the most general type of lung cancer, accounting for more than 85% of all lung cancers. 1,2 Although chemotherapy and radiotherapy have improved lung cancer treatment over the past few decades, survival rates remain poor, with approximately 15% of patients remaining alive at 5 years after diagnosis. This poor prognosis is due to metastasis in the late stage of disease. Cells with a stem-like, dormant phenotype, endowed with unlimited self-renewal and high tumorigenic capability, are deemed responsible for post-therapy relapse and metastatic dissemination in various cancers, including lung cancer. 3-5 Therefore, the drugs that attack the cancer stem cells (CSCs) population have therapeutic benefit.Melatonin (N-acetyl-5-methoxytryptamine), a hormone secreted by the pineal grand and other organs, is produced in a circadian rhythm in reply to photic signaling from the retina. 6,7 Melatonin is important for controlling the immune system 8-10 and has an antioxidant effect. 11,12 This agent protects cells against carcinogenic substances and inhibits the development, metastasis, invasion and angiogenesis of many types

show abstract

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

Cited by 48 publications

References 126 publications

Ras inhibitors display an anti-metastatic effect by downregulation of lysyl oxidase through inhibition of the Ras-PI3K-Akt-HIF-1α pathway

Ras inhibitors display an anti-metastatic effect by downregulation of lysyl oxidase through inhibition of the Ras-PI3K-Akt-HIF-1α pathway

Genes associated with increased brain metastasis risk in non–small cell lung cancer: Comprehensive genomic profiling of 61 resected brain metastases versus primary non–small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036)

Melatonin reduces lung cancer stemness through inhibiting of PLC, ERK, p38, β‐catenin, and Twist pathways

Contact Info

Product

Resources

About