Dataset Information

Fucoidan Rescues p-Cresol-Induced Cellular Senescence in Mesenchymal Stem Cells via FAK-Akt-TWIST Axis.

ABSTRACT: Mesenchymal stem cells (MSCs) are a source for cell-based therapy. Although MSCs have the potential for tissue regeneration, their therapeutic efficacy is restricted by the uremic toxin, p-cresol, in chronic kidney disease (CKD). To address this issue, we investigated the effect of fucoidan, a marine sulfated polysaccharide, on cellular senescence in MSCs. After p-cresol exposure, MSC senescence was induced, as indicated by an increase in cell size and a decrease in proliferation capacity. Treatment of senescent MSCs with fucoidan significantly reversed this cellular senescence via regulation of SMP30 and p21, and increased proliferation through the regulation of cell cycle-associated proteins (CDK2, CDK4, cyclin D1, and cyclin E). These effects were dependent on FAK-Akt-TWIST signal transduction. In particular, fucoidan promoted the expression of cellular prion protein (PrP^C), which resulted in the maintenance of cell expansion capacity in p-cresol-induced senescent MSCs. This protective effect of fucoidan on senescence-mediated inhibition of proliferation was dependent on the TWIST-PrP^C axis. In summary, this study shows that fucoidan protects against p-cresol-induced cellular senescence in MSCs through activation of the FAK-Akt-TWIST pathway and suggests that fucoidan could be used in conjunction with functional MSC-based therapies in the treatment of CKD.

SUBMITTER: Lee JH

PROVIDER: S-EPMC5923408 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Fucoidan Rescues p-Cresol-Induced Cellular Senescence in Mesenchymal Stem Cells via FAK-Akt-TWIST Axis.

Lee Jun Hee JH Yun Chul Won CW Hur Jin J Lee Sang Hun SH

Marine drugs 20180406 4

Mesenchymal stem cells (MSCs) are a source for cell-based therapy. Although MSCs have the potential for tissue regeneration, their therapeutic efficacy is restricted by the uremic toxin, <i>p</i>-cresol, in chronic kidney disease (CKD). To address this issue, we investigated the effect of fucoidan, a marine sulfated polysaccharide, on cellular senescence in MSCs. After <i>p</i>-cresol exposure, MSC senescence was induced, as indicated by an increase in cell size and a decrease in proliferation c ...[more]

PMID: 29642406

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Project description:The bipolar androgen therapy (BAT) to treat prostate cancer includes cycles of supraphysiological androgen levels (SAL) under continuous androgen deprivation therapy (ADT). We showed previously that SAL induces cellular senescence in androgen-sensitive PCa cells and ex vivo in PCa tumor samples from patients that underwent radical prostatectomy. Here, we show that SAL induces cellular senescence in both, castration sensitive (CSPC) LNCaP and castration resistant PCa (CRPC) C4-2 cells through the cell cycle inhibitor p15. Treatment with the Akt inhibitor (Akti) potently inhibited SAL-induced expression of p15 and cellular senescence in both cell lines. Proximity ligation assays (PLA) combined with high-resolution laser-scanning microscopy indicate that SAL promotes interaction of endogenous androgen receptor (AR) with endogenous Akt in cytoplasm as well as in nucleus after 72 hours hormone treatment. This suggests that the AR interacts with Akt also in a long-term manner. Transcriptome sequencing (RNA-seq) comparing the SAL-induced transcriptomes of LNCaP with C4-2 cells as well as of Akti treated cells revealed landscapes for cell senescence. Interestingly, one of the identified genes is the lncRNASAT1. SAL treatment of native patient tumor samples ex vivo results in upregulation of lncRNASAT1. The lncRNASAT1 is down-regulated in PCa tumor tissues compared to non-tumor tissues of same patients indicating a tumor suppressive function. Knockdown indicates that the lncRNASAT1 is crucial for SAL-induced cancer cell senescence and regulates LNCaP cell proliferation being an upstream factor for pAkt and for p15. Further, knockdown of lncRNASAT1 inhibits LNCaP cell proliferation by low androgen levels but enhances proliferation by SAL. This suggests that lncRNASAT1 serves as a tumor suppressor with SAL. Interestingly, immunoprecipitation of AR detected lncRNASAT1 as an AR interacting partner that regulates AR target gene expression. Thus, we identified a novel pathway of androgen signaling as the AR- lncRNASAT1- Akt- p15INK4b- axis to mediate SAL-induced cellular senescence.

Dataset Information

Fucoidan Rescues p-Cresol-Induced Cellular Senescence in Mesenchymal Stem Cells via FAK-Akt-TWIST Axis.

Publications

Fucoidan Rescues p-Cresol-Induced Cellular Senescence in Mesenchymal Stem Cells via FAK-Akt-TWIST Axis.

Similar Datasets

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