Ras inhibition amplifies cisplatin sensitivity of human glioblastoma

Resistance to chemotherapy is a common feature of malignant gliomas. This resistance is mediated by receptor tyrosine kinase (RTK)-regulated signaling. p21-Ras protein is pivotal in the propagation of the signal originated from many RTKs. Our aim was to investigate whether inhibition of Ras pathway...

Full description

Saved in:
Bibliographic Details
Published in:Biochemical and biophysical research communications 2004-07, Vol.320 (2), p.493-500
Main Authors: Messina, Samantha, Leonetti, Carlo, De Gregorio, Giorgia, Affatigato, Valentina, Ragona, Giuseppe, Frati, Luigi, Zupi, Gabriella, Santoni, Angela, Porcellini, Antonio
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Adenovirus
Animals
Antineoplastic Agents - pharmacology
Apoptosis
Brain Neoplasms - pathology
Cell Line, Tumor
Chemotherapy
Cisplatin - pharmacology
Drug resistance
Enzyme Activation
Gene therapy
Glioblastoma
Glioblastoma - pathology
Humans
Male
Mice
Mice, Nude
Neoplasm Transplantation
Phosphatidylinositol 3-Kinases - metabolism
Protein-Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Ras
ras Proteins - antagonists & inhibitors
ras Proteins - genetics
Signal transduction
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Resistance to chemotherapy is a common feature of malignant gliomas. This resistance is mediated by receptor tyrosine kinase (RTK)-regulated signaling. p21-Ras protein is pivotal in the propagation of the signal originated from many RTKs. Our aim was to investigate whether inhibition of Ras pathway affects the response to cisplatin in malignant gliomas. We found an enhanced sensitivity to cisplatin of two glioblastoma cell lines expressing dominant negative Ras. Moreover, DN-Ras expressing cells, implanted in nude mice, resulted in being extremely sensitive to cisplatin. The growth of all the tumors was significantly inhibited by combining DN-Ras adenovirus infection with cisplatin treatment. The majority of glioma cells expressing DN-Ras underwent apoptosis in response to cisplatin. In vivo, DN-Ras alone did not influence the growth of tumors, suggesting that the effects of Ras-inhibition observed in vitro could not be extrapolated in vivo. The survival signal pathway transduced by Ras was essentially mediated by inhibition of caspase-9 cleavage via PI3K/Akt.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2004.06.003