Elucidating the role of the FoxO3a transcription factor in the IGF-1-induced migration and invasion of uveal melanoma cancer cells

Yan, F.; Liao, Rifang; Farhan, Mohd; Wang, Tinghuai; Chen, Jiashu; Wang, Zhong; Little, Peter J.; Zheng, Wenhua

doi:10.1016/j.biopha.2016.11.027

Cited by 31 publications

(31 citation statements)

References 58 publications

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“…Akt phosphorylates FoxO3a and promoted its retention in the cytoplasm, thus prevented cell regulatory actions which took place in the nucleus. In contrast, Akt inhibition induced FoxO3a dephosphorylation and promoted its translocation from the cytoplasm into the nucleus 35,37 . To explore the effect of Pristimerin on cellular shuttling of FoxO3a, UM‐1 cells were transfected with GFP‐FoxO3a.…”

Section: Resultsmentioning

confidence: 99%

Pristimerin‐induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway

Yan

Liao

Silva³

et al. 2020

J Cellular Molecular Medi

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Uveal melanoma (UM) is a highly invasive intraocular malignancy with high mortality. Presently, there is no FDA‐approved standard for the treatment of metastatic UM. Pristimerin is a natural quinine methide triterpenoid compound with anti‐angiogenic, anti‐cancer and anti‐inflammatory activities. However, Pristimerin potential cytotoxic effect on UM was poorly investigated. In the present study, we found the migration and invasion of UM‐1 cells were inhibited by Pristimerin which also caused a rapid increase of ROS, decreased mitochondrial membrane potential, induced the accumulation of cells in G0/G1 phase, ending with apoptotic cell death. Pristimerin inhibited Akt and FoxO3a phosphorylation and induced nuclear accumulation of FoxO3a in UM‐1 cells, increased the expression of pro‐apoptotic proteins Bim、p27Kip1, cleaved caspase‐3, PARP and Bax, and decreased the expression of Cyclin D1 and Bcl‐2. LY294002 or Akt‐siRNA inhibited the PI3K/Akt/FoxO3a pathway and promoted the Pristimerin‐induced apoptosis, while Pristimerin effects were partially abolished in FoxO3a knockdown UM‐1 cell cultures. Taken together, present results showed that Pristimerin induced apoptotic cell death through inhibition of PI3K/Akt/FoxO3a pathway in UM‐1 cells. These findings indicate that Pristimerin may be considered as a potential chemotherapeutic agent for patients with UM.

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Section: Resultsmentioning

confidence: 99%

Pristimerin‐induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway

Yan

Liao

Silva³

et al. 2020

J Cellular Molecular Medi

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“…JC‐1 dye was used to monitor mitochondrial integrity, as described by Yan et al . (). In brief, D407 cells were seeded into black 96‐well plates (1 × 10 4 cells per well).…”

Section: Methodsmentioning

confidence: 97%

Insulin‐like growth factor‐1 activates PI3K/Akt signalling to protect human retinal pigment epithelial cells from amiodarone‐induced oxidative injury

Liao

Yan

Zhuanping

et al. 2017

British J Pharmacology

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Amiodarone is one of the most effective anti-arrhythmic drugs available, but its clinical applications are limited by toxic side effects including optic toxicity. The purpose of this study was to investigate the toxic effect of amiodarone on D407 cells (a human retinal pigmented epithelial (RPE) cell line) and the mechanisms of the protective effect of insulin-like growth factor-1 (IGF-1). EXPERIMENTAL APPROACHThe involvement of the kinases, Akt and ERK, was analysed by Western blot. Intracellular accumulation of ROS was measured using fluorophotometric quantification. A pharmacological approach with inhibitors was used to investigate the pathways involved in the protective action of IGF-1. KEY RESULTSAmiodarone concentration-dependently augmented the production of ROS, lipid peroxidation and apoptosis in D407 cells. IGF-1 time-and concentration-dependently reversed these effects of amiodarone and protected D407 cells from amiodarone-mediated toxicity. Amiodarone inhibited the pAkt but not pErk, and IGF-1 reversed this inhibitory effect of amiodarone. However, IGF-1 failed to suppress amiodarone-induced cytotoxicity in the presence of PI3K/Akt inhibitor LY294002 suggesting the direct involvement of the PI3K/Akt pathway. Furthermore, in vivo rat flash electroretinogram (FERG) recordings showed that IGF-1 reverses the amiodarone-induced decrease in a-and b-waves. The immunocytochemistry findings confirmed that vitreous IGF-1 injections promote the survival of RPE cells in rat retina treated with amiodarone. CONCLUSION AND IMPLICATIONSIGF-1 can protect RPE cells from amiodarone-mediated injury via the PI3K/Akt pathway in vivo and in vitro. IGF-1 has potential as a protective drug for the prevention and treatment of amiodarone-induced optic toxicity.Abbreviations FERG, flash electroretinogram; IGF-1, insulin-like growth factor-1; INL, inner nuclear layer; IPL, inner plexiform layer; RGCs, retinal ganglionic cells; RPE, retinal pigmented epithelium

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“…Previous studies have reported that FOXO3a is a downstream factor of PI3K/AKT that inhibits the survival, growth, migration and invasion of uveal melanoma cells, as well as inducing cell cycle arrest at G1 phase and apoptosis by transcriptionally regulating the expression of its downstream genes, including Bcl-2-like protein 11, cyclin-dependent kinase inhibitor 1B, survivin and cyclin D1 (21,23,24,36). Furthermore, FOXO3a triple mutant overexpression sensitized melanoma cells to apoptosis induced by temozolomide (22).…”

Section: Discussionmentioning

confidence: 99%

“…These results were consistent with previous reports. However, in addition to transcriptionally regulated genes related to cell cycle and apoptosis (21,23,24,36), there was an alternative mechanism for FOXO3a in the development of melanoma; it was observed that FOXO3a regulated aerobic glycolysis by regulating the expression of SIRT6, which is recognized as a major regulator of cellular metabolism in cancer (8).…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that FOXO3a is also an important regulator of cellular metabolism in tumors; for example, FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression in colon cancer (20). Additionally, FOXO3a has been shown to regulate multiple cellular process, including cell survival, apoptosis (21)(22)(23), migration and invasion (24) in melanoma. However, the role of FOXO3a in the regulation of cellular metabolism in melanoma has never been explored.…”

Section: Introductionmentioning

confidence: 99%

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FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma

Dong

Yang

et al. 2020

Int J Oncol

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Melanoma, the most aggressive human skin tumor, has a very short survival time, and there are currently no effective treatments. Alterations in cell metabolism, such as enhanced aerobic glycolysis, have been identified as hallmarks of cancer cells. In the present study, bioinformatics studies using online databases revealed that FOXO3a expression was lower in melanoma tissues compared with normal tissues and nevus. Additionally, Kaplan-Meier analysis showed that high expression of FOXO3a predicted an improved prognosis for patients with melanoma. Furthermore, Pearson correlation analysis indicated that the expression of FOXO3a was positively correlated with SIRT6 expression and negatively correlated with the expression levels of a number of glycolysis-associated genes. Chromatin immunoprecipitation and luciferase assays showed that FOXO3a was enriched in the SIRT6 promoter region and promoted its transcription. Then, SIRT6 was overexpressed in FOXO3a-knockdown MV3 cells and downregulated in FOXO3a-overexpressing MV3 cells by using lentivirus-mediated stable infection. The results showed that SIRT6 knockdown or overexpression rescued the effects of FOXO3a overexpression or knockdown, respectively, on glycolysis, as determined by glucose uptake, glucose consumption and lactate production assays, the expression of glycolytic genes and glucose stress flux tests. SIRT6 overexpression also suppressed FOXO3a knockdown-induced tumor growth in a mouse model. The present findings indicated that the FOXO3a-SIRT6 regulatory axis inhibited glucose metabolism and tumor cell proliferation in melanoma, and provided novel insight into potential therapeutic strategies to treat this disease.

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Elucidating the role of the FoxO3a transcription factor in the IGF-1-induced migration and invasion of uveal melanoma cancer cells

Cited by 31 publications

References 58 publications

Pristimerin‐induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway

Pristimerin‐induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway

Insulin‐like growth factor‐1 activates PI3K/Akt signalling to protect human retinal pigment epithelial cells from amiodarone‐induced oxidative injury

FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma

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