Akt Regulated Phosphorylation of GSK-3β/Cyclin D1, p21 and p27 Contributes to Cell Proliferation Through Cell Cycle Progression From G1 to S/G2M Phase in Low-Dose Arsenite Exposed HaCat Cells

Chen, Yao; Liu, Xudan; Wang, Huanhuan; Liu, Shiyi; Hu, Nannan; Li, Xin

doi:10.3389/fphar.2019.01176

Cited by 41 publications

(20 citation statements)

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“…After DNA damage without repair, cells cannot pass the G1 checkpoint formed by p21 and p53, replication and accumulation of damaged DNA was suppressed ( 20 ). p27 mainly binds to cyclin to inhibit cyclin-CDK complex to block cell cycle progression and cell division ( 21 ). Therefore, we guess that Krm2 promotes cell cycle progression by regulating p21 and p27.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Kremen2 Inhibits Tumor Growth and Migration in Gastric Cancer

et al. 2021

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Kremen2 (Krm2) plays an important role in embryonic development, bone formation, and tumorigenesis as a crucial regulator of classical Wnt/β-catenin signaling pathway. However, the role of Krm2 in gastric cancer is not clear. The aim of this study was to explore the regulatory role of Krm2 in the tumorigenesis and metastasis of gastric cancer. It was demonstrated that, compared to para-cancerous tissues, Krm2 was significantly up-regulated in gastric cancer tissues and was positively correlated with the pathological grade of gastric cancer patients. Given that Krm2 is abundantly expressed in most tested gastric cancer cell lines, Krm2 knockdown cell models were established and further used to construct mice xenograft model. After knocking down Krm2, both the cell survival in vitro and tumorigenesis in vivo of gastric cancer cells were inhibited. At the same time, knockdown of Krm2 induced apoptosis, cell cycle arrest at G2/M phase and repression of migration in gastric cancer cells in vitro. Mechanistically, we found that knockdown of Krm2 suppressed PI3K/Akt pathway. Therefore, we revealed the novel role and the molecular mechanism of Krm2 in promoting the tumorigenesis and metastasis in gastric cancer. Krm2 can be a potent candidate for designing of targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Knockdown of Kremen2 Inhibits Tumor Growth and Migration in Gastric Cancer

et al. 2021

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“…Similarly, cyclin E and CDK2/4/6 also play key roles in the G0/G1 transition in the cell cycle [ 37 – 40 ]. Furthermore, p21 and p27 act by binding CDK in the G1 phase of the cell cycle, leading to inhibition of the phosphorylation of other proteins such as retinoblastoma, which is necessary for cell cycle progression [ 41 , 42 ]. In our study, protein analysis showed the decreased expression of cyclin D1/E and CDK2/4/6, and increased expression of p21 and p27 proteins.…”

Section: Discussionmentioning

confidence: 99%

10-HDA Induces ROS-Mediated Apoptosis in A549 Human Lung Cancer Cells by Regulating the MAPK, STAT3, NF-κB, and TGF-β1 Signaling Pathways

Lin

Liu

Luo

et al. 2020

BioMed Research International

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10-Hydroxy-2-decenoic acid (10-HDA), also known as royal jelly acid, has a variety of physiological functions, and recent studies have shown that it also has anticancer effects. However, its anticancer mechanisms have not been clearly defined. In this study, we investigated the underlying mechanisms of 10-HDA in A549 human lung cancer cells. We used Cell Counting Kit-8 assay, scratch wound healing assay, flow cytometry, and western blot analysis to investigate its apoptotic effects and underlying mechanism. Our results showed that 10-HDA inhibited the proliferation of three types of human lung cancer cells and had no significant toxic effects on normal cells. Accompanying reactive oxygen species (ROS), 10-HDA induced A549 cell apoptosis by regulating mitochondrial-associated apoptosis, and caused cell cycle arrest at the G0/G1 phase in a time-dependent manner. Meanwhile, 10-HDA also regulated mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) signaling pathways by increasing the expression levels of phosphorylated c-Jun N-terminal kinase, p-p38, and I-κB, and additionally, by decreasing the expression levels of phosphorylated extracellular signal-regulated kinase, p-STAT3, and NF-κB. These effects were blocked by MAPK inhibitors and N-acetyl-L-cysteine. Furthermore, 10-HDA inhibited cell migration by regulating transforming growth factor beta 1 (TGF-β1), SNAI1, GSK-3β, E-cadherin, N-cadherin, and vimentin. Taken together, the results of this study showed that 10-HDA induced cell cycle arrest and apoptosis in A549 human lung cancer cells through ROS-mediated MAPK, STAT3, NF-κB, and TGF-β1 signaling pathways. Therefore, 10-HDA may be a potential therapy for human lung cancer.

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“…In its key components, conserved from unicellular eukaryotic organisms to higher vertebrates and humans, the PI3K/AKT pathway converts nutrient and growth factor sensing on the plasma membrane into downstream effector functions within the cell [ 52 ]. Central metabolic stimuli, including glutamate as an indicator of amino acid availability [ 53 ] and insulin as a surrogate marker of sugar [ 54 ], trigger TORC1-dependent protein synthesis as a fundamentum of mass growth [ 53 , 55 , 56 ], and cyclin kinase-driven cell cycle progression as a pacemaker of adjusted proliferation [ 57 , 58 ]. For a more comprehensive overview, please refer to Figure 1 , which illustrates external trigger factors, key signaling components, and central output relays jointly understood as manifestations of PI3K/AKT signaling.…”

Section: The Pi3k/akt/sox2 Axis In Stemness Reprogramming and Camentioning

confidence: 99%

SOX2 and p53 Expression Control Converges in PI3K/AKT Signaling with Versatile Implications for Stemness and Cancer

Schaefer

Steiner

Lengerke

2020

IJMS

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Stemness and reprogramming involve transcriptional master regulators that suppress cell differentiation while promoting self-renewal. A distinguished example thereof is SOX2, a high mobility group (HMG)-box transcription factor (TF), whose subcellular localization and turnover regulation in embryonic, induced-pluripotent, and cancer stem cells (ESCs, iPSCs, and CSCs, respectively) is mediated by the PI3K/AKT/SOX2 axis, a stem cell-specific branch of the PI3K/AKT signaling pathway. Further effector functions associated with PI3K/AKT induction include cell cycle progression, cellular (mass) growth, and the suppression of apoptosis. Apoptosis, however, is a central element of DNA damage response (DDR), where it provides a default mechanism for cell clearance when DNA integrity cannot be maintained. A key player in DDR is tumor suppressor p53, which accumulates upon DNA-damage and is counter-balanced by PI3K/AKT enforced turnover. Accordingly, stemness sustaining SOX2 expression and p53-dependent DDR mechanisms show molecular–functional overlap in PI3K/AKT signaling. This constellation proves challenging for stem cells whose genomic integrity is a functional imperative for normative ontogenesis. Unresolved mutations in stem and early progenitor cells may in fact provoke transformation and cancer development. Such mechanisms are also particularly relevant for iPSCs, where genetic changes imposed through somatic cell reprogramming may promote DNA damage. The current review aims to summarize the latest advances in the understanding of PI3K/AKT/SOX2-driven stemness and its intertwined relations to p53-signaling in DDR under conditions of pluripotency, reprogramming, and transformation.

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Akt Regulated Phosphorylation of GSK-3β/Cyclin D1, p21 and p27 Contributes to Cell Proliferation Through Cell Cycle Progression From G1 to S/G2M Phase in Low-Dose Arsenite Exposed HaCat Cells

Cited by 41 publications

References 41 publications

Knockdown of Kremen2 Inhibits Tumor Growth and Migration in Gastric Cancer

Knockdown of Kremen2 Inhibits Tumor Growth and Migration in Gastric Cancer

10-HDA Induces ROS-Mediated Apoptosis in A549 Human Lung Cancer Cells by Regulating the MAPK, STAT3, NF-κB, and TGF-β1 Signaling Pathways

SOX2 and p53 Expression Control Converges in PI3K/AKT Signaling with Versatile Implications for Stemness and Cancer

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