RasGTPase-activating protein is a target of caspases in spontaneous apoptosis of lung carcinoma cells and in response to etoposide

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Serval ID
serval:BIB_12CA56E63A1F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
RasGTPase-activating protein is a target of caspases in spontaneous apoptosis of lung carcinoma cells and in response to etoposide
Journal
Carcinogenesis
Author(s)
Bartling  B., Yang  J. Y., Michod  D., Widmann  C., Lewensohn  R., Zhivotovsky  B.
ISSN
0143-3334 (Print)
Publication state
Published
Issued date
06/2004
Volume
25
Number
6
Pages
909-21
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jun
Abstract
p120 RasGTPase-activating protein (RasGAP), the main regulator of Ras GTPase family members, is cleaved at low caspase activity into an N-terminal fragment that triggers potent anti-apoptotic signals via activation of the Ras/PI-3 kinase/Akt pathway. When caspase activity is increased, RasGAP fragment N is further processed into two fragments that effectively potentiate apoptosis. Expression of RasGAP protein and its cleavage was assessed in human lung cancer cells with different histology and responsiveness to anticancer drug-induced apoptosis. Here we show that therapy-sensitive small lung carcinoma cell (SCLC) lines have lower RasGAP expression levels and higher spontaneous cleavage with formation of fragment N compared to therapy-resistant non-small cell lung carcinoma cell (NSCLC) lines. The first RasGAP cleavage event strongly correlated with the increased level of spontaneous apoptosis in SCLC. However, generation of protective RasGAP fragment N also related to the potency of SCLC to develop secondary therapy-resistance. In response to etoposide (ET), RasGAP fragment N was further cleaved in direct dependence on caspase-3 activity, which was more pronounced in NSCLC cells. Caspase inhibition, while effectively preventing the second cleavage of RasGAP, barely affected the first cleavage of RasGAP into fragment N that was always detectable in NSCLC and SCLC cells. These findings suggest that different levels of RasGAP and fragment N might play a significant role in the biology and different clinical course of both subtypes of lung neoplasms. Furthermore, constitutive formation of RasGAP fragment N can potentially contribute to primary resistance of NSCLC to anticancer therapy by ET but also to secondary therapy-resistance in SCLC.
Keywords
*Apoptosis Carcinoma, Non-Small-Cell Lung/enzymology/*metabolism/pathology Carcinoma, Small Cell/enzymology/*metabolism/pathology Caspases/*metabolism Cell Line, Tumor Enzyme Activation Etoposide/*pharmacology Humans Lung Neoplasms/enzymology/*metabolism/pathology ras GTPase-Activating Proteins/*metabolism
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 14:43
Last modification date
25/09/2019 6:08
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