scholarly journals Inhibition of protein phosphatase 2A with a small molecule LB100 radiosensitizes nasopharyngeal carcinoma xenografts by inducing mitotic catastrophe and blocking DNA damage repair

Oncotarget ◽  
2014 ◽  
Vol 5 (17) ◽  
pp. 7512-7524 ◽  
Author(s):  
Peng Lv ◽  
Yue Wang ◽  
Jie Ma ◽  
Zheng Wang ◽  
Jing-Li Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nasopharyngeal Carcinoma ◽  
Small Molecule ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Dna Damage Repair ◽  
Mitotic Catastrophe ◽  
Damage Repair ◽  
Phosphatase 2A

scholarly journals Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

2019 ◽  
Vol 20 (19) ◽  
pp. 4728 ◽  
Author(s):  
Hwani Ryu ◽  
Hyun-Kyung Choi ◽  
Hyo Jeong Kim ◽  
Ah-Young Kim ◽  
Jie-Young Song ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Tyrosine Kinase ◽  
Small Molecule ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Class Iii ◽  
Damage Repair ◽  
Repair Genes

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the ‘BRCAness’/‘DNA-PKness’ phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

Abstract 5329: Development of small molecule activators of protein phosphatase 2A for the treatment of lung cancer

2015 ◽  
Author(s):  
Jaya Sangodkar ◽  
Sudeh Izadmehr ◽  
Sahar Mahzar ◽  
Divya Hoon ◽  
Shen Yao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Molecule ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Phosphatase 2A

scholarly journals CDK4/6 Inhibitor Palbociclib Amplifies the Radiosensitivity to Nasopharyngeal Carcinoma Cells via Mediating Apoptosis and Suppressing DNA Damage Repair

2019 ◽  
Vol Volume 12 ◽  
pp. 11107-11117 ◽  
Author(s):  
Xianhe Xie ◽  
Weili Zheng ◽  
Ting Chen ◽  
Wanzun Lin ◽  
Ziyuan Liao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nasopharyngeal Carcinoma ◽  
Dna Damage Repair ◽  
Carcinoma Cells ◽  
Damage Repair

scholarly journals Protein Phosphatase 2A Antagonizes ATM and ATR in a Cdk2- and Cdc7-Independent DNA Damage Checkpoint

2006 ◽  
Vol 26 (5) ◽  
pp. 1997-2011 ◽  
Author(s):  
Paris Petersen ◽  
Danny M. Chou ◽  
Zhongsheng You ◽  
Tony Hunter ◽  
Johannes C. Walter ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Protein Phosphatase ◽  
Ataxia Telangiectasia ◽  
Protein Phosphatase 2A ◽  
Inhibitory Effect ◽  
Dna Damage Checkpoint ◽  
Free System ◽  
Phosphatase 2A ◽  
Initiation Of Dna Replication

ABSTRACT We previously used a soluble cell-free system derived from Xenopus eggs to investigate the role of protein phosphatase 2A (PP2A) in chromosomal DNA replication. We found that immunodepletion of PP2A or inhibition of PP2A by okadaic acid (OA) inhibits initiation of DNA replication by preventing loading of the initiation factor Cdc45 onto prereplication complexes. Evidence was provided that PP2A counteracts an inhibitory protein kinase that phosphorylates and inactivates a crucial Cdc45 loading factor. Here, we report that the inhibitory effect of OA is abolished by caffeine, an inhibitor of the checkpoint kinases ataxia-telangiectasia mutated protein (ATM) and ataxia-telangiectasia related protein (ATR) but not by depletion of ATM or ATR from the extract. Furthermore, we demonstrate that double-strand DNA breaks (DSBs) cause inhibition of Cdc45 loading and initiation of DNA replication and that caffeine, as well as immunodepletion of either ATM or ATR, abolishes this inhibition. Importantly, the DSB-induced inhibition of Cdc45 loading is prevented by addition of the catalytic subunit of PP2A to the extract. These data suggest that DSBs and OA prevent Cdc45 loading through different pathways, both of which involve PP2A, but only the DSB-induced checkpoint implicates ATM and ATR. The inhibitory effect of DSBs on Cdc45 loading does not result from downregulation of cyclin-dependent kinase 2 (Cdk2) or Cdc7 activity and is independent of Chk2. However, it is partially dependent on Chk1, which becomes phosphorylated in response to DSBs. These data suggest that PP2A counteracts ATM and ATR in a DNA damage checkpoint in Xenopus egg extracts.

scholarly journals Protein Phosphatase 2A Inhibition with LB100 Enhances Radiation-Induced Mitotic Catastrophe and Tumor Growth Delay in Glioblastoma

2015 ◽  
Vol 14 (7) ◽  
pp. 1540-1547 ◽  
Author(s):  
Ira K. Gordon ◽  
Jie Lu ◽  
Christian A. Graves ◽  
Kristin Huntoon ◽  
Jason M. Frerich ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Mitotic Catastrophe ◽  
Growth Delay ◽  
Tumor Growth Delay ◽  
Phosphatase 2A ◽  
Radiation Induced

scholarly journals Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer

2018 ◽  
Vol 78 (8) ◽  
pp. 2065-2080 ◽  
Author(s):  
Kimberly McClinch ◽  
Rita A. Avelar ◽  
David Callejas ◽  
Sudeh Izadmehr ◽  
Danica Wiredja ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Molecule ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phosphatase 2A

scholarly journals VEGF knockdown enhances radiosensitivity of nasopharyngeal carcinoma by inhibiting autophagy through the activation of mTOR pathway

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Li Chen ◽  
Guoxiang Lin ◽  
Kaihua Chen ◽  
Fangzhu Wan ◽  
Renba Liang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nasopharyngeal Carcinoma ◽  
Western Blotting ◽  
Dna Damage Repair ◽  
Xenograft Model ◽  
Mtor Pathway ◽  
Angiogenic Factor ◽  
Cell Counting ◽  
Damage Repair

Abstract Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. VEGF was reported to promote the occurrence of autophagy, which enhanced the radioresistance of tumors. The purpose of this study was to investigate the influence of VEGF silencing on the radiosensitivity of nasopharyngeal carcinoma (NPC) cells and the underlying mechanisms. The radiosensitivity of NPC cells after VEGF silencing was detected by cell counting kit 8 (CCK-8) and clonogenic assay, while cell cycle and apoptosis were detected by flow cytometry. The processes of DNA damage, repair and autophagy were examined by immunofluorescence and western blotting. The interaction between VEGF and mTOR was confirmed by western blotting and co-immunoprecipitation studies. The effect of VEGF on radiosensitivity of NPC cells was investigated in vivo using a xenograft model. Furthermore, immunohistochemistry and TUNEL assays were used to verify the relationship between autophagy and radiosensitivity in NPC after VEGF depletion. Downregulation of VEGF significantly inhibited cell proliferation and induced apoptosis of NPC cells after radiotherapy in vitro and in vivo. In addition, VEGF knockdown not only decreased autophagy level, but also delayed the DNA damage repair in NPC cells after irradiation. Mechanistically, silencing VEGF suppressed autophagy through activation of the mTOR pathway. VEGF depletion increased radiosensitivity of NPC cells by suppressing autophagy via activation of the mTOR pathway.

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