scholarly journals Expression of 1N3R-Tau Isoform Inhibits Cell Proliferation by Inducing S Phase Arrest in N2a Cells

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0119865 ◽  
Author(s):  
Li Li ◽  
Zhi-Peng Xu ◽  
Gong-Ping Liu ◽  
Cheng Xu ◽  
Zhi-Hao Wang ◽  
...  
Endocrinology ◽  
1993 ◽  
Vol 133 (5) ◽  
pp. 2403-2406 ◽  
Author(s):  
P Smerdely ◽  
V Pitsiavas ◽  
S C Boyages

2018 ◽  
Vol 108 ◽  
pp. 925-933 ◽  
Author(s):  
Jia-Li Wang ◽  
Qinghua Quan ◽  
Ruifang Ji ◽  
Xiao-Yu Guo ◽  
Jia-Mei Zhang ◽  
...  

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2894-2894 ◽  
Author(s):  
Ritika Dutta ◽  
Maria Castellanos ◽  
Bruce Tiu ◽  
Hee-Don Chae ◽  
Kara L. Davis ◽  
...  

Abstract The 90 kDa Ribosomal S6 Kinase (RSK), downstream of the ERK signaling pathway, has recently been implicated in a wide variety of cancers, ranging from lung cancer to medulloblastoma, as a driver of cancer cell proliferation and survival. However, its role in Acute Myeloid Leukemia (AML) remains unknown. Thus, the goal of this study was to characterize RSK-dependent signaling pathways in AML, with the overall hypothesis that disruption of this pathway represents a potential strategy for the treatment of AML. The RSK family consists of four gene isoforms, RSK1-4 (RPS6KA1 (RSK1), RPS6KA2 (RSK3), RPS6KA3 (RSK2), RPS6KA4 (RSK4). Knockdown (KD) of RSK1 by shRNA in HL-60 and KG-1 cell lines resulted in reduced AML cell growth in vitro. NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were injected with 2x106 HL-60 or KG-1 RSK1KD cells and vector control transduced cells in order to investigate the effects of RSK1 KD on AML cell growth and survival in vivo. Mice injected with RSK1 KD cells exhibited prolonged survival by 17 and 21 days respectively for HL-60 and KG-1 cell induced disease (p=0.0023 and 0.0018 respectively). These data indicate that RSK1 knockdown inhibits leukemia progression, and RSK1 is required for maximal proliferation of AML cells in vivo. Pharmacological inhibition of total RSK (RSK1-4) by the small molecule inhibitor BI-D1870 reduced AML cell growth and induced cell death in both AML cell lines and patient samples after treatment for 48 hours. The IC50 for growth inhibition was 1.8 uM for MOLM-13, 1.6 uM for MV-4-11, and 1.9 uM for HL-60 cells. In methylcellulose colony assays, normal hematopoietic stem and progenitor cell proliferation was not affected by RSK inhibition up to a concentration of 15 uM, establishing an approximately 10-fold therapeutic index. To elucidate the mechanism by which RSK inhibition suppresses AML proliferation, we performed cell cycle analysis with HL-60 cells. RSK inhibition by BI-D1870 resulted in delayed S-phase progression and accumulation of cells in late S-phase with increased pH2AX, cPARP, and CDK2/Cyclin A expression, as measured by flow cytometry. These data indicate that inhibition of RSK leads to activation of DNA damage pathways and arrest in S-phase, resulting in apoptosis. Inhibition of CDK activity rescued S-phase arrest, demonstrating that activation and dysregulation of CDK are crucial mediators of RSK inhibitor-induced S-phase arrest. In summary, this is the first study to demonstrate that RSK plays an important role in maintaining AML cell survival and proliferation and to position RSK as a promising target for treatment of AML. Disclosures No relevant conflicts of interest to declare.


Gene ◽  
2018 ◽  
Vol 679 ◽  
pp. 232-240 ◽  
Author(s):  
Jia-Peng Li ◽  
Xing-Hua Liao ◽  
Yuan Xiang ◽  
Ao Yao ◽  
Ru-Hui Song ◽  
...  

2019 ◽  
Vol 20 (13) ◽  
pp. 3197 ◽  
Author(s):  
Takanori Matsui ◽  
Taiga Chiyo ◽  
Hideki Kobara ◽  
Shintaro Fujihara ◽  
Koji Fujita ◽  
...  

Esophageal squamous cell carcinoma (ESCC) is the most common primary esophageal malignancy. Telmisartan, an angiotensin II type 1 (AT1) receptor blocker (ARB) and a widely used antihypertensive, has been shown to inhibit proliferation of various cancer types. This study evaluated the effects of telmisartan on human ESCC cell proliferation in vitro and in vivo and sought to identify the microRNAs (miRNAs) involved in these antitumor effects. We examined the effects of telmisartan on three human ESCC cell lines (KYSE150, KYSE180, and KYSE850). Telmisartan inhibited proliferation of these three cell lines by inducing S-phase arrest, which was accompanied by decreased expression of cyclin A2, cyclin-dependent kinase 2, and other cell cycle-related proteins. Additionally, telmisartan reduced levels of phosphorylated ErbB3 and thrombospondin-1 in KYSE180 cells. Furthermore, expression of miRNAs was remarkably altered by telmisartan in vitro. Telmisartan also inhibited tumor growth in vivo in a xenograft mouse model. In conclusion, telmisartan inhibited cell proliferation and tumor growth in ESCC cells by inducing cell-cycle arrest.


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