Forkhead box protein O3 suppresses uveal melanoma development by increasing the expression of Bcl‑2‑like protein 11 and cyclin‑dependent kinase inhibitor 1B

Yan, F.; Liao, Rifang; Lin, Shaofen; Deng, Xiaomin; Little, Peter J.; Zheng, Wenhua

doi:10.3892/mmr.2017.8215

Cited by 5 publications

(6 citation statements)

References 30 publications

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“…In the next step, we investigated the effects of PI3K/Akt and FoxO3a inhibitors on Pristimerin effects on phosphorylation and expression protein level of FoxO3a, a transcriptional factor that regulates gene expression, essential for cell cycle arrest and apoptosis in its dephosphorylated form in a nuclear location 35,36 . Figure 7A‐D indicated that both LY294002 and Akt siRNA treatments strongly potentiated the inhibitory effect of 3 μM Pristimerin on Akt (Ser473) and FoxO3a (Ser253) phosphorylations, when compared to the respective control groups.…”

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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“…Another report also found the pristimerin-induced melanoma cell death via inhibiting PI3K/Akt/FOXO3 signalling pathway [42]. Fengxia Yan also found that FOXO3 suppressed melanoma development by increasing the expression of Bcl2like protein 11 (BCL2L11) and cyclindependent kinase inhibitor 1B (CDKN1B) [43]. By consulting the existing literature, we found that FOXO3 did play an anti-tumor role in UVM.…”

Section: Discussionmentioning

confidence: 68%

A Pan-Cancer Analysis of Transcription Factor Forkhead Box O-3: FOXO3

Cai

Li²,

Yang

et al. 2021

Preprint

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Background: Although available cell - or animal- based evidence supports the relationship between transcription factor FOXO3 and cancers, so far, there has been no pan-cancer analysis of FOXO3. Methods: We thus first carry on a pan-cancer analysis of FOXO3 across multiple tumors via several online websites based on the datasets of TCGA, including statistical correlations of FOXO3 expression with clinical prognosis, protein phosphorylation, cancer-associated fibroblasts infiltration, tumor mutational burden, and relevant cellular pathway. Results: FOXO3 was usually as an anti-tumor gene in KIRC, BLCA, CESC, UVM, LUAD and BRCA cancers, while a higher level of FOXO3 may have a certain cancer-promoting effect. As FOXO3 usually played a cancer-promoting role in ERα- BRCA but in ERα+ BRCA played an anti-tumor role, which may be due to transcription factor ERα translocating FOXO3 to the cytoplasm to weaken the transcription activity of FOXO3. FOXO3 activates autophagy related genes through transcription to maintain the occurrence of basal autophagy when basal autophagy is inhibited. However, FOXO3 can also induce apoptosis through transcription of pro-apoptotic genes if autophagy inhibition persists. The expression of phosphorylated FOXO3 protein at different sites may also affect its transcriptional activity by changing its shuttle between nucleus and cytoplasm. Therefore, When we analyze the functions of FOXO3 in a specific type of cancer, we should combine with the expression of FOXO3, the alteration status of FOXO3, the overall phosphorylation status of FOXO3, the basic autophagy status, the expression levels of ERα, SIRT1, CBP, FKBP5, RERE and SMAD4, and cancer-associated fibroblasts subtype, even consider the KRAS mutation, P53 mutation or non-genetic factors which can influence the functions of cancer-associated fibroblasts in the specific type of cancer. Conclusions: Our first pan-cancer study has provided a relatively comprehensive understanding of the role of FOXO3 in different tumors, and will give some help and enlightenment to later researchers who study the role of FOXO3 in various cancers.

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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%

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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Forkhead box protein O3 suppresses uveal melanoma development by increasing the expression of Bcl‑2‑like protein 11 and cyclin‑dependent kinase inhibitor 1B

Cited by 5 publications

References 30 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

A Pan-Cancer Analysis of Transcription Factor Forkhead Box O-3: FOXO3

FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma

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