scholarly journals CEP131 Abrogates CHK1 Inhibitor-Induced Replication Defects and Is Associated with Unfavorable Outcome in Neuroblastoma

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Kiyohiro Ando ◽  
Verna Cázares-Ordoñez ◽  
Makoto Makishima ◽  
Atsushi Yokoyama ◽  
Yusuke Suenaga ◽  
...  
Keyword(s):  
Dna Damage ◽  
Therapeutic Strategy ◽  
Neuroblastoma Cell ◽  
Mass Spectrometry Analysis ◽  
Spectrometry Analysis ◽  
Checkpoint Kinase 1 ◽  
Family Protein ◽  
Damage Response ◽  
Chk1 Inhibitor ◽  
Associated Family

Checkpoint kinase 1 (CHK1) plays a key role in genome surveillance and integrity throughout the cell cycle. Selective inhibitors of CHK1 (CHK1i) are undergoing clinical evaluation for various human malignancies, including neuroblastoma. Recently, we reported that CHK1i, PF-477736, induced a p53-mediated DNA damage response. As a result, the cancer cells were able to repair DNA damage and became less sensitive to CHK1i. In this study, we discovered that PF-477736 increased expression of MDM2 oncogene along with CHK1i-induced replication defects in neuroblastoma NB-39-nu cells. A mass spectrometry analysis of protein binding to MDM2 in the presence of CHK1i identified the centrosome-associated family protein 131 (CEP131), which was correlated with unfavorable prognosis of neuroblastoma patients. We revealed that MDM2 was associated with CEP131 protein degradation, whereas overexpression of CEP131 accelerated neuroblastoma cell growth and exhibited resistance to CHK1i-induced replication defects. Thus, these findings may provide a future therapeutic strategy against centrosome-associated oncogenes involving CEP131 as a target in neuroblastoma.

scholarly journals The Olsenella Uli Induced Pneumonia: A Case Report

2021 ◽  
Author(s):  
Yufen Yan ◽  
Hong Li ◽  
Shuai Li ◽  
Shuhui Liu ◽  
Nan Jia ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Pulmonary Infection ◽  
Mass Spectrometry Analysis ◽  
Causative Role ◽  
Positive Bacterium ◽  
Spectrometry Analysis ◽  
First Case ◽  
Infection Treatment ◽  
Third Generation Cephalosporins

Abstract Olsenella uli is a Gram-positive bacterium common in the oral cavity or gastrointestinal tract. Here we reported a first case of human pneumonia caused by the Olsenella uli. The identification of Olsenella uli was based on micromorphology, sequence analysis and mass spectrometry analysis of the bacteria recovered from sputum. Ceftazidime，one of the third generation cephalosporins was used for the anti-infection treatment of the patient. CT results showed a significant improvement of the pulmonary lesion and pleural effusion and recovery from pulmonary infection after 10 days. The mechanism underlying Olsenella uli induced pneumonia is unclear, our report suggests a causative role of gingival bacteria in pathogenesis of pneumonia, and the intervention by Ceftazidime may offer a therapeutic strategy for Olsenella uli infection.

scholarly journals Role of GOLPH3 and TPX2 in Neuroblastoma DNA Damage Response and Cell Resistance to Chemotherapy

2019 ◽  
Vol 20 (19) ◽  
pp. 4764 ◽  
Author(s):  
Marzia Ognibene ◽  
Marina Podestà ◽  
Alberto Garaventa ◽  
Annalisa Pezzolo
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Preschool Age ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Therapeutic Benefits ◽  
Damage Response

Neuroblastoma (NB) is an aggressive, relapse-prone infancy tumor of the sympathetic nervous system and is the leading cause of death among preschool age diseases, so the search for novel therapeutic targets is crucial. Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in the development, and in the DNA damage response, of various human cancers. Golgi dispersal is a common feature of DNA damage response in mammalian cells. Understanding how cells react to DNA damage is essential in order to recognize the systems used to escape from elimination. We induced DNA damage in two human neuroblastoma cell lines by curcumin. The exposure of neuroblastoma cells to curcumin induced: (a) up-regulation of GOLPH3+ cells; (b) augmentation of double-strand breaks; (c) Golgi fragmentation and dispersal throughout the cytoplasm; (d) increase of apoptosis and autophagy; (e) increased expression of TPX2 oncoprotein, able to repair DNA damage. Primary neuroblastoma samples analysis confirmed these observations. Our findings suggest that GOLPH3 expression levels may represent a clinical marker of neuroblastoma patients’ responsiveness to DNA damaging therapies—and of possible resistance to them. Novel molecules able to interfere with GOLPH3 and TPX2 pathways may have therapeutic benefits when used in combination with standard DNA damaging therapeutic agents in neuroblastoma

scholarly journals NTRK1/TrkA Activation Overrides the G2/M-Checkpoint upon Irradiation

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6023
Author(s):  
Christina Hassiepen ◽  
Aashish Soni ◽  
Ines Rudolf ◽  
Vivian Boron ◽  
Sebastian Oeck ◽  
...  
Keyword(s):  
Dna Damage ◽  
Neuroblastoma Cell ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Checkpoint Activation ◽  
Neuronal Precursor Cells ◽  
Damage Response ◽  
High Doses ◽  
Neuroblastoma Cell Lines

High expression of the receptor tyrosine kinase TrkA/NTRK1 is associated with a favorable outcome in several solid tumors of childhood including neuroblastoma. During development, TrkA/NTRK1 governs migration and differentiation of neuronal precursor cells, while it is associated with mitotic dysfunction and altered DNA damage response, among others, in neuroblastoma. Here, we used human neuroblastoma cell lines with inducible TrkA/NTRK1 expression to mechanistically explore the role of TrkA/NTRK1 signaling in checkpoint activation after DNA damage induced by ionizing radiation (IR). TrkA/NTRK1 activated cells showed increased short-term cell viability upon IR compared to vector control cells. This was accompanied by a deficient G2/M-checkpoint at both low (1 Gy) and high doses (4 Gy) of IR. In a tightly controlled setting, we confirmed that this effect was strictly dependent on activation of TrkA/NTRK1 by its ligand, nerve growth factor (NGF). TrkA/NTRK1-expressing cells displayed impaired ATM and CHK1 phosphorylation, resulting in stabilization of CDC25B. In line with these findings, ATM or ATR inhibition recapitulated the effects of TrkA/NTRK1 activation on the IR-induced G2/M-checkpoint. In conclusion, we here provide first evidence for a previously unrecognized function of NTRK signaling in checkpoint regulation and the response to IR.

scholarly journals Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells

2009 ◽  
Vol 8 (1) ◽  
pp. 45-54 ◽  
Author(s):  
Leslie A. Parsels ◽  
Meredith A. Morgan ◽  
Daria M. Tanska ◽  
Joshua D. Parsels ◽  
Brian D. Palmer ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Checkpoint Kinase ◽  
Checkpoint Kinase 1 ◽  
Pancreatic Cancer Cells ◽  
Damage Response
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