Induction of G2/M Cell Cycle Arrest and Apoptosis by Genistein in Human Bladder Cancer T24 Cells through Inhibition of the ROS-Dependent PI3k/Akt Signal Transduction Pathway

We examined the anti-cancer effect of genistein, a soy-derived isoflavone, in human bladder transitional cell carcinoma T24 cells. According to our data, genistein induced G2/M phase arrest of the cell cycle and apoptosis. Genistein down-regulated the levels of cyclin A and cyclin B1, but up-regulated the levels of p21WAF1/CIP1, cyclin-dependent kinase (Cdk) inhibitor, that was complexed with Cdc2 and Cdk2. Furthermore, genistein induced the activation of caspases (caspase-3, -8 and -9), and cleavage of poly (ADP-ribose) polymerase cleavage. However, genistein-induced apoptosis was significantly inhibited by a pan-caspase inhibitor, indicating that the induction of apoptosis by genestein was caspase-dependent. In addition, genistein increased the cytosolic release of cytochrome c by increasing the Bax/Bcl-2 ratio and destroying mitochondria integrity. Moreover, genistein inactivated the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, while LY294002, a PI3K/Akt inhibitor, increased the apoptosis-inducing effect of genistein. Genistein further increased the accumulation of reactive oxygen species (ROS), which was significantly suppressed by N-acetyl cysteine (NAC), a ROS scavenger, and in particular, NAC prevented genistein-mediated inactivation of PI3K/Akt signaling, G2/M arrest and apoptosis. Therefore, the present results indicated that genistein promoted apoptosis induction in human bladder cancer T24 cells, which was associated with G2/M phase cell cycle arrest via regulation of ROS-dependent PI3K/Akt signaling pathway.

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Tubeimoside-1 upregulates p21 expression and induces apoptosis and G2/M phase cell cycle arrest in human bladder cancer T24 cells

Bangladesh Journal of Pharmacology ◽

10.3329/bjp.v9i4.19989 ◽

2014 ◽

Vol 9 (4) ◽

Cited By ~ 2

Author(s):

Azhar Rasul ◽

Xiaoyan Shen ◽

Bingyu Wang ◽

Bao Liu ◽

Xiaomeng Li ◽

...

Keyword(s):

Cell Cycle ◽

Bladder Cancer ◽

Cell Cycle Arrest ◽

Phase Cell ◽

Human Bladder Cancer ◽

Human Bladder ◽

Cycle Arrest ◽

T24 Cells ◽

M Phase

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Jaceosidin inhibits proliferation of human bladder cancer T24 cells through induction of cell cycle arrest and apoptosis

Bangladesh Journal of Pharmacology ◽

10.3329/bjp.v8i3.15620 ◽

2013 ◽

Vol 8 (3) ◽

Cited By ~ 2

Author(s):

Yong Li ◽

Yan Tan

Keyword(s):

Cell Cycle ◽

Bladder Cancer ◽

Cell Cycle Arrest ◽

Human Bladder Cancer ◽

Human Bladder ◽

Cycle Arrest ◽

T24 Cells

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Oxymatrine inhibits proliferation of human bladder cancer T24 cells by inducing apoptosis and cell cycle arrest

Oncology Letters ◽

10.3892/ol.2017.6013 ◽

2017 ◽

Vol 13 (6) ◽

pp. 4453-4458 ◽

Cited By ~ 9

Author(s):

Shun Li ◽

Yi Zhang ◽

Qingyong Liu ◽

Qingli Zhao ◽

Liuyu Xu ◽

...

Keyword(s):

Cell Cycle ◽

Bladder Cancer ◽

Cell Cycle Arrest ◽

Human Bladder Cancer ◽

Human Bladder ◽

Cycle Arrest ◽

T24 Cells

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Anti-Proliferative and Pro-Apoptotic Effects of Licochalcone A through ROS-Mediated Cell Cycle Arrest and Apoptosis in Human Bladder Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20153820 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3820 ◽

Cited By ~ 2

Author(s):

Su Hyun Hong ◽

Hee-Jae Cha ◽

Hyun Hwang-Bo ◽

Min Yeong Kim ◽

So Young Kim ◽

...

Keyword(s):

Cell Cycle ◽

Bladder Cancer ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Human Bladder Cancer ◽

Human Bladder ◽

Cycle Arrest ◽

Bladder Cancer Cells ◽

M Phase ◽

Human Bladder Cancer Cells

Licochalcone A (LCA) is a chalcone that is predominantly found in the root of Glycyrrhiza species, which is widely used as an herbal medicine. Although previous studies have reported that LCA has a wide range of pharmacological effects, evidence for the underlying molecular mechanism of its anti-cancer efficacy is still lacking. In this study, we investigated the anti-proliferative effect of LCA on human bladder cancer cells, and found that LCA induced cell cycle arrest at G2/M phase and apoptotic cell death. Our data showed that LCA inhibited the expression of cyclin A, cyclin B1, and Wee1, but increased the expression of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP1, and increased p21 was bound to Cdc2 and Cdk2. LCA activated caspase-8 and -9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and also increased caspase-3 activity, a typical effect caspase, subsequently leading to poly (ADP-ribose) polymerase cleavage. Additionally, LCA increased the Bax/Bcl-2 ratio, and reduced the integrity of mitochondria, which contributed to the discharge of cytochrome c from the mitochondria to the cytoplasm. Moreover, LCA enhanced the intracellular levels of reactive oxygen species (ROS); however, the interruption of ROS generation using ROS scavenger led to escape from LCA-mediated G2/M arrest and apoptosis. Collectively, the present data indicate that LCA can inhibit the proliferation of human bladder cancer cells by inducing ROS-dependent G2/M phase arrest and apoptosis.

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Betulinic Acid Restricts Human Bladder Cancer Cell Proliferation In Vitro by Inducing Caspase-Dependent Cell Death and Cell Cycle Arrest, and Decreasing Metastatic Potential

Molecules ◽

10.3390/molecules26051381 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1381

Author(s):

So Young Kim ◽

Hyun Hwangbo ◽

Min Yeong Kim ◽

Seon Yeong Ji ◽

Da Hye Kim ◽

...

Keyword(s):

Cell Cycle ◽

Bladder Cancer ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Human Bladder Cancer ◽

Human Bladder ◽

Cycle Arrest ◽

Bladder Cancer Cells ◽

Induced Apoptosis ◽

Human Bladder Cancer Cells

Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid and generally found in the bark of birch trees (Betula sp.). Although several studies have been reported that BA has diverse biological activities, including anti-tumor effects, the underlying anti-cancer mechanism in bladder cancer cells is still lacking. Therefore, this study aims to investigate the anti-proliferative effect of BA in human bladder cancer cell lines T-24, UMUC-3, and 5637, and identify the underlying mechanism. Our results showed that BA induced cell death in bladder cancer cells and that are accompanied by apoptosis, necrosis, and cell cycle arrest. Furthermore, BA decreased the expression of cell cycle regulators, such as cyclin B1, cyclin A, cyclin-dependent kinase (Cdk) 2, cell division cycle (Cdc) 2, and Cdc25c. In addition, BA-induced apoptosis was associated with mitochondrial dysfunction that is caused by loss of mitochondrial membrane potential, which led to the activation of mitochondrial-mediated intrinsic pathway. BA up-regulated the expression of Bcl-2-accociated X protein (Bax) and cleaved poly-ADP ribose polymerase (PARP), and subsequently activated caspase-3, -8, and -9. However, pre-treatment of pan-caspase inhibitor markedly suppressed BA-induced apoptosis. Meanwhile, BA did not affect the levels of intracellular reactive oxygen species (ROS), indicating BA-mediated apoptosis was ROS-independent. Furthermore, we found that BA suppressed the wound healing and invasion ability, and decreased the expression of Snail and Slug in T24 and 5637 cells, and matrix metalloproteinase (MMP)-9 in UMUC-3 cells. Taken together, this is the first study showing that BA suppresses the proliferation of human bladder cancer cells, which is due to induction of apoptosis, necrosis, and cell cycle arrest, and decrease of migration and invasion. Furthermore, BA-induced apoptosis is regulated by caspase-dependent and ROS-independent pathways, and these results provide the underlying anti-proliferative molecular mechanism of BA in human bladder cancer cells.

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