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Inhibition of RalA signaling pathway in treatment of non-small cell lung cancer.
MedLine Citation:
PMID:  22498113     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and relatively resistant to chemotherapy. The most prevalent molecular abnormality in NSCLC is the overactivation of K-Ras proto-oncogene; therefore, elucidating down-stream Ras signaling in NSCLC is significantly important in developing novel therapies against this malignancy. Our work indicates that RalA, an important effector of Ras, is activated in NSCLC cell lines. While RalA was also overactivated in fetal human broncho-epithelial cells, RalBP1 (Ral binding protein-1), an important down-stream effector of RalA, was expressed at higher levels in cancer cell lines. Aurora kinase-A (AKA), an upstream activator of RalA, was also found to be active only in malignant cells. The outcome of inhibition of RalA (by gene specific silencing using a lentivirus) on the malignant phenotype of A549 cells was also studied. While proliferation and invasiveness of A549 cells were reduced upon silencing RalA, apoptosis and necrosis were elevated in such conditions. Additionally, the in vivo tumorigenesis of A549 cells was reduced upon partial inhibition of RalA and AKA using pharmacological inhibitors. Finally, we were interested in evaluating the level of active RalA in the fraction of NSCLC cells expressing cancer stem cell markers. For this purpose cells with increased expression of CD44 were separated from A549 cells and compared with cells with low level of expression of this marker and an unsorted population. A significant enhancement of RalA activation in high CD44+ cells was found as potential evidence for involvement of RalA signaling in initiation of the neoplastic procedure and an important contributor for tumor maintenance in NSCLC. Further studies can reveal therapeutic, preventive and diagnostic value of RalA pathway in this deadly disease.
Authors:
Heather Male; Vijay Patel; Mark A Jacob; Emma Borrego-Diaz; Kun Wang; Derek A Young; Amanda L Wise; Chao Huang; Peter Van Veldhuizen; Amy O'Brien-Ladner; Stephen K Williamson; Sarah A Taylor; Ossama Tawfik; Tuba Esfandyari; Faris Farassati
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-10
Journal Detail:
Title:  Lung cancer (Amsterdam, Netherlands)     Volume:  -     ISSN:  1872-8332     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8800805     Medline TA:  Lung Cancer     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Affiliation:
The University of Kansas Medical Center, Department of Medicine - Divisions of Hematology/Oncology & Gastroenterology, Molecular Medicine Laboratory, Kansas City, KS, USA.
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