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-regulat...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-08-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/8/9/327 |
| _version_ | 1797708529200529408 |
|---|---|
| author | Cheol Park Hee-Jae Cha Hyesook Lee Hyun Hwang-Bo Seon Yeong Ji Min Yeong Kim Su Hyun Hong Jin-Woo Jeong Min Ho Han Sung Hyun Choi Cheng-Yun Jin Gi-Young Kim Yung Hyun Choi |
| author_facet | Cheol Park Hee-Jae Cha Hyesook Lee Hyun Hwang-Bo Seon Yeong Ji Min Yeong Kim Su Hyun Hong Jin-Woo Jeong Min Ho Han Sung Hyun Choi Cheng-Yun Jin Gi-Young Kim Yung Hyun Choi |
| author_sort | Cheol Park |
| collection | DOAJ |
| description | 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 <i>c</i> 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. |
| first_indexed | 2024-03-12T06:23:01Z |
| format | Article |
| id | doaj.art-730c7447def24d2592940dafdcd9f78b |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-12T06:23:01Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-730c7447def24d2592940dafdcd9f78b2023-09-03T02:05:36ZengMDPI AGAntioxidants2076-39212019-08-018932710.3390/antiox8090327antiox8090327Induction 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 PathwayCheol Park0Hee-Jae Cha1Hyesook Lee2Hyun Hwang-Bo3Seon Yeong Ji4Min Yeong Kim5Su Hyun Hong6Jin-Woo Jeong7Min Ho Han8Sung Hyun Choi9Cheng-Yun Jin10Gi-Young Kim11Yung Hyun Choi12Department of Molecular Biology, College of Natural Sciences, Dong-eui University, Busan 47340, KoreaDepartment of Parasitology and Genetics, Kosin University College of Medicine, Busan 49267, KoreaAnti-Aging Research Center, Dong-eui University, Busan 47340, KoreaAnti-Aging Research Center, Dong-eui University, Busan 47340, KoreaAnti-Aging Research Center, Dong-eui University, Busan 47340, KoreaAnti-Aging Research Center, Dong-eui University, Busan 47340, KoreaAnti-Aging Research Center, Dong-eui University, Busan 47340, KoreaFreshwater Bioresources Utilization Bureau, Nakdonggang National Institute of Biological Resources, Sangju 37242, KoreaNational Marine Biodiversity Institute of Korea, Seocheon 33662, KoreaDepartment of System Management, Korea Lift College, Geochang 50141, KoreaSchool of Pharmaceutical Sciences, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Henan 450001, ChinaDepartment of Marine Life Sciences, Jeju National University, Jeju 63243, KoreaAnti-Aging Research Center, Dong-eui University, Busan 47340, KoreaWe 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 <i>c</i> 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.https://www.mdpi.com/2076-3921/8/9/327genisteinG2/M arrestapoptosisROSPI3K/Akt |
| spellingShingle | Cheol Park Hee-Jae Cha Hyesook Lee Hyun Hwang-Bo Seon Yeong Ji Min Yeong Kim Su Hyun Hong Jin-Woo Jeong Min Ho Han Sung Hyun Choi Cheng-Yun Jin Gi-Young Kim Yung Hyun Choi 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 Antioxidants genistein G2/M arrest apoptosis ROS PI3K/Akt |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | genistein G2/M arrest apoptosis ROS PI3K/Akt |
| url | https://www.mdpi.com/2076-3921/8/9/327 |
| work_keys_str_mv | AT cheolpark inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT heejaecha inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT hyesooklee inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT hyunhwangbo inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT seonyeongji inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT minyeongkim inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT suhyunhong inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT jinwoojeong inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT minhohan inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT sunghyunchoi inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT chengyunjin inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT giyoungkim inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway AT yunghyunchoi inductionofg2mcellcyclearrestandapoptosisbygenisteininhumanbladdercancert24cellsthroughinhibitionoftherosdependentpi3kaktsignaltransductionpathway |