Carcinogenesis Advance Access published online on January 23, 2004
Carcinogenesis, doi:10.1093/carcin/bgh075
© 2004 by Oxford University Press
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CANCER BIOLOGY
1 Institute of Environmental Medicine, Division of Toxicology; Karolinska Institutet, Stockholm, Sweden
* Corresponding author. E-mail: boris.zhivotovsky{at}imm.ki.se.
Received 14 October 2003
; revised 2 December 2003
; accepted 19 December 2003
p120 RasGTPase-activating protein (RasGAP), the main regulator of Ras GTPase family members, is cleaved at low caspase activity into a 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 anti-cancer 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 N fragment 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, 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 anti-cancer therapy by etoposide but also to secondary therapy-resistance in SCLC.
lung cancer, RasGAP, etoposide, apoptosis
RasGTPase-activating protein is a target of caspases in spontaneous apoptosis of lung carcinoma cells and in response to etoposide
2 Institut de Biologie Cellulaire et de Morphologie, Université de Lausanne, Lausanne, Switzerland
3 Institute of Oncology and Pathology, Unit of Medical Radiobiology, Cancer Centre Karolinska R8:00; Karolinska Institutet, Stockholm, Sweden
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