Downregulation of MTHFD2 Inhibits the Progression of Bladder Cancer Through PI3K/AKT Signaling Pathways

Abstract Background: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is related to the pathogenesis of many human malignant tumors, but its role in bladder cancer remains poorly understood. We aimed to determine the effect of downregulation of MTHFD2 on the progression of bladder cancer. First, the relationship between MTHFD2 expression and survival time in patients with bladder cancer was analyzed by GEPIA and the UALCAN online database. The expression of MTHFD2 in bladder cancer and adjacent tissues was detected by reverse transcription-quantitative PCR (RT-PCR), Western blot (WB), and tissue microarray. Second, the effects of low expression of MTHFD2 on the proliferation of bladder cancer cell lines were evaluated by CCK-8, Transwell, cell wound scratch, cell cloning, and flow cytometry assays. In vivo, the effect of MTHFD2 silencing on tumorigenicity was determined in nude mice. Furthermore, the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt) signaling pathway was confirmed by western blotting after RNA sequencing (RNA-seq). Results: The expression of MTHFD2 in bladder cancer tissues was significantly higher and positively correlated with tumor stage and negatively correlated with overall survival. The expression of MTHFD2 in bladder cancer lines was significantly higher and the proliferation, migration, and clone formation ability of bladder cancer cells with low expression of MTHFD2 were significantly decreased in vitro and in vivo. RNA-seq showed that the differential genes were enriched in the PI3K/Akt signaling pathway. WB revealed that the expression of PI3K/AKT protein was downregulated. Conclusions: Our findings indicated that downregulation of MTHFD2 can reduce the progression of bladder cancer through inhibited PI3K-AKT signal pathway and may be provided a new approach for the diagnosis and treatment of bladder cancer.

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ISL1 promoted tumorigenesis and EMT via Aurora kinase A-induced activation of PI3K/AKT signaling pathway in neuroblastoma

Cell Death and Disease ◽

10.1038/s41419-021-03894-3 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Mengzhen Li ◽

Chengtao Sun ◽

Xiaoyun Bu ◽

Yi Que ◽

Lian Zhang ◽

...

Keyword(s):

Cell Proliferation ◽

Signaling Pathway ◽

Malignant Tumors ◽

Aurora Kinase ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Aurora Kinase A ◽

Kinase A

AbstractNeuroblastoma (NB) is the most common extracranial solid malignancy in children and its mortality rate is relatively high. However, driver genes of NB are not clearly identified. Using bioinformatics analysis, we determined the top 8 differentially expressed genes (DEGs) in NB, including GFAP, PAX6, FOXG1, GAD1, PTPRC, ISL1, GRM5, and GATA3. Insulin gene enhancer binding protein 1 (ISL1) is a LIM homeodomain transcription factor which has been found to be highly expressed in a variety of malignant tumors, but the function of ISL1 in NB has not been fully elucidated. We identified ISL1 as an oncogene in NB. ISL1 is preferentially upregulated in NB tissues compared with normal tissues. High ISL1 expression is significantly associated with poor outcome of NB patients. Knockdown of ISL1 markedly represses proliferation and induces cell apoptosis in vitro, and suppresses tumorigenicity in vivo, while overexpression of ISL1 has the opposite effects. Mechanistically, we demonstrate that ISL1 promotes cell proliferation and EMT transformation through PI3K/AKT signaling pathway by upregulating Aurora kinase A (AURKA), a serine-threonine kinase that is essential for the survival of NB cells. The blockade of AURKA attenuates the function of ISL1 overexpression in the regulation of cell proliferation and migration, Conclusively, this study showed that ISL1 targeted AURKA to facilitate the development of NB, which provided new insights into the tumorigenesis of NB. Thus, ISL1 may be a promising therapeutic target in the future.

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Oxysterol binding protein-like 3 (OSBPL3) is a novel driver gene that promotes tumor growth in part through R-Ras/Akt signaling in gastric cancer

Scientific Reports ◽

10.1038/s41598-021-98485-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Qingjiang Hu ◽

Takaaki Masuda ◽

Kensuke Koike ◽

Kuniaki Sato ◽

Taro Tobo ◽

...

Keyword(s):

Gastric Cancer ◽

Signaling Pathway ◽

Malignant Tumors ◽

Clinical Analysis ◽

Akt Signaling ◽

Driver Gene ◽

Akt Signaling Pathway ◽

Driver Genes

AbstractGastric cancer (GC) is one of the most lethal malignant tumors. To improve the prognosis of GC, the identification of novel driver genes as therapeutic targets is in urgent need. Here, we aimed to identify novel driver genes and clarify their roles in gastric cancer. OSBPL3 was identified as a candidate driver gene by in silico analysis of public genomic datasets. OSBPL3 expression was analyzed by RT-qPCR and immunohistochemistry in GC cells and tissues. The biological functions and mechanisms of OSBPL3 in GC were examined in vitro and in vivo using GC cells. The association between OSBPL3 expression and clinical outcome in GC patients was also evaluated. Overexpression of OSBPL3 was detected in GC cells with OSBPL3 DNA copy number gains and promoter hypomethylation. OSBPL3-knockdown reduced GC cell growth in vitro and in vivo by inhibiting cell cycle progression. Moreover, an active Ras pull-down assay and western blotting demonstrated that OSBPL3 activates the R-Ras/Akt signaling pathway in GC cells. In a clinical analysis of two GC datasets, high OSBPL3 expression was predictive of a poor prognosis. Our findings suggest that OSBPL3 is a novel driver gene stimulating the R-Ras/Akt signaling pathway and a potential therapeutic target in GC patients.

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Squamosamide derivative FLZ protected dopaminergic neuron by activating Akt signaling pathway in 6-OHDA-induced in vivo and in vitro Parkinson's disease models

Brain Research ◽

10.1016/j.brainres.2013.12.026 ◽

2014 ◽

Vol 1547 ◽

pp. 49-57 ◽

Cited By ~ 17

Author(s):

Xiu-Qi Bao ◽

Xiang-Chen Kong ◽

Li-Bing Kong ◽

Liang-Yu Wu ◽

Hua Sun ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Signaling Pathway ◽

Dopaminergic Neuron ◽

Akt Signaling ◽

Disease Models ◽

Akt Signaling Pathway

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A77 1726 (leflunomide) blocks and reverses cardiac hypertrophy and fibrosis in mice

Clinical Science ◽

10.1042/cs20180160 ◽

2018 ◽

Vol 132 (6) ◽

pp. 685-699 ◽

Cited By ~ 20

Author(s):

Zhen-Guo Ma ◽

Xin Zhang ◽

Yu-Pei Yuan ◽

Ya-Ge Jin ◽

Ning Li ◽

...

Keyword(s):

T Cell ◽

Cardiac Hypertrophy ◽

Protective Effect ◽

Signaling Pathway ◽

Cardiac Fibrosis ◽

Pressure Overload ◽

Akt Signaling ◽

Akt Signaling Pathway

T-cell infiltration and the subsequent increased intracardial chronic inflammation play crucial roles in the development of cardiac hypertrophy and heart failure (HF). A77 1726, the active metabolite of leflunomide, has been reported to have powerful anti-inflammatory and T cell-inhibiting properties. However, the effect of A77 1726 on cardiac hypertrophy remains completely unknown. Herein, we found that A77 1726 treatment attenuated pressure overload or angiotensin II (Ang II)-induced cardiac hypertrophy in vivo, as well as agonist-induced hypertrophic response of cardiomyocytes in vitro. In addition, we showed that A77 1726 administration prevented induction of cardiac fibrosis by inhibiting cardiac fibroblast (CF) transformation into myofibroblast. Surprisingly, we found that the protective effect of A77 1726 was not dependent on its T lymphocyte-inhibiting property. A77 1726 suppressed the activation of protein kinase B (AKT) signaling pathway, and overexpression of constitutively active AKT completely abolished A77 1726-mediated cardioprotective effects in vivo and in vitro. Pretreatment with siRNA targetting Fyn (si Fyn) blunted the protective effect elicited by A77 1726 in vitro. More importantly, A77 1726 was capable of blocking pre-established cardiac hypertrophy in mice. In conclusion, A77 1726 attenuated cardiac hypertrophy and cardiac fibrosis via inhibiting FYN/AKT signaling pathway.

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Cyanidin inhibits EMT induced by oxaliplatinviatargeting the PDK1–PI3K/Akt signaling pathway

Food & Function ◽

10.1039/c8fo01611a ◽

2019 ◽

Vol 10 (2) ◽

pp. 592-601 ◽

Cited By ~ 6

Author(s):

Xiang Li ◽

Ze-sheng Zhang ◽

Xiao-han Zhang ◽

Sheng-nan Yang ◽

Dong Liu ◽

...

Keyword(s):

Antitumor Activity ◽

Signaling Pathway ◽

Akt Signaling ◽

Akt Signaling Pathway

Anthocyanins have been shown to exhibit antitumor activity in several cancersin vitroandin vivo.

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In vitro and in vivo Induction of p53-Dependent Apoptosis by Extract of Euryale ferox Salisb in A549 Human Caucasian Lung Carcinoma Cancer Cells Is Mediated Through Akt Signaling Pathway

Frontiers in Oncology ◽

10.3389/fonc.2019.00406 ◽

2019 ◽

Vol 9 ◽

Cited By ~ 2

Author(s):

Gun-He Nam ◽

Kyung-Jo Jo ◽

Ye-Seul Park ◽

Hye Won Kawk ◽

Sang-Yong Kim ◽

...

Keyword(s):

Cancer Cells ◽

Signaling Pathway ◽

Lung Carcinoma ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Euryale Ferox ◽

In Vivo Induction

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Luteolin Exerts Cardioprotective Effects through Improving Sarcoplasmic Reticulum Ca2+-ATPase Activity in Rats during Ischemia/Reperfusion In Vivo

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/365854 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 9

Author(s):

Changsheng Nai ◽

Haochen Xuan ◽

Yingying Zhang ◽

Mengxiao Shen ◽

Tongda Xu ◽

...

Keyword(s):

Sarcoplasmic Reticulum ◽

Signaling Pathway ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Akt Signaling ◽

Myocardial Infarct Size ◽

Akt Signaling Pathway ◽

Cardioprotective Effects

The flavonoid luteolin exists in many types of fruits, vegetables, and medicinal herbs. Our previous studies have demonstrated that luteolin reduced ischemia/reperfusion (I/R) injury in vitro, which was related with sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity. However, the effects of luteolin on SERCA2a activity during I/R in vivo remain unclear. To investigate whether luteolin exerts cardioprotective effects and to monitor changes in SERCA2a expression and activity levels in vivo during I/R, we created a myocardial I/R rat model by ligating the coronary artery. We demonstrated that luteolin could reduce the myocardial infarct size, lactate dehydrogenase release, and apoptosis during I/R injury in vivo. Furthermore, we found that luteolin inhibited the I/R-induced decrease in SERCA2a activity in vivo. However, neither I/R nor luteolin altered SERCA2a expression levels in myocardiocytes. Moreover, the PI3K/Akt signaling pathway played a vital role in this mechanism. In conclusion, the present study has confirmed for the first time that luteolin yields cardioprotective effects against I/R injury by inhibiting the I/R-induced decrease in SERCA2a activity partially via the PI3K/Akt signaling pathway in vivo, independent of SERCA2a protein level regulation. SERCA2a activity presents a novel biomarker to assess the progress of I/R injury in experimental research and clinical applications.

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