Carcinogenesis Advance Access originally published online on January 23, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis, Vol. 25, No. 6, 909-921,
June 2004
Carcinogenesis vol.25 no.6 © Oxford University Press 2004; all rights reserved.
ARTICLE |
RasGTPase-activating protein is a target of caspases in spontaneous apoptosis of lung carcinoma cells and in response to etoposide
1 Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Stockholm, Sweden, 2 Institut de Biologie Cellulaire et de Morphologie, Université de Lausanne, Lausanne, Switzerland and 3 Institute of Oncology and Pathology, Unit of Medical Radiobiology, Cancer Centre Karolinska R8:00, Karolinska Institutet, Stockholm, Sweden
4 To whom correspondence should be addressed. Email: boris.zhivotovsky{at}imm.ki.se
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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J.-Y. Yang, J. Walicki, D. Michod, G. Dubuis, and C. Widmann Impaired Akt Activity Down-Modulation, Caspase-3 Activation, and Apoptosis in Cells Expressing a Caspase-resistant Mutant of RasGAP at Position 157 Mol. Biol. Cell, August 1, 2005; 16(8): 3511 - 3520. [Abstract] [Full Text] [PDF]
|
|