TY - JOUR
T1 - Mitochondrial dysfunction is an essential step for killing of non-small cell lung carcinomas resistant to conventional treatment
AU - Joseph, Bertrand
AU - Marchetti, Philippe
AU - Formstecher, Pierre
AU - Kroemer, Guido
AU - Lewensohn, Rolf
AU - Zhivotovsky, Boris
N1 - Funding Information:
The authors are very grateful to Prof Sten Orrenius for support and Drs R Jemmerson and PH Kramer for providing antibodies. This work was supported by grants from the Swedish Cancer Society (3829-B98-03XAC), the Stockholm Cancer Society (98:119) and INSERM-MRC. B Joseph was supported by a Fellowship from Association de Recherche contre le Cancer.
PY - 2002/1/1
Y1 - 2002/1/1
N2 - Apoptosis, a tightly controlled multi-step mechanism of cell death, is important for anti-cancer therapy-based elimination of tumor cells. However, this process is not always efficient. Small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) cells display different susceptibility to undergo apoptosis induced by anticancer treatment. In contrast to SCLC, NSCLC cells are cross-resistant to a broad spectrum of apoptotic stimuli, including receptor stimulation, cytotoxic drugs and γ-radiation. Since resistance of tumor cells to treatment often accounts for the failure of traditional forms of cancer therapy, in the present study attempts to find a potent broad-range apoptosis inductor, which can kill therapy-resistant NSCLC cells were undertaken and the mechanism of apoptosis induction by this drug was investigated in detail. We found that staurosporine (STS) had cell killing effect on both types of lung carcinomas. Release of cytochrome c, activation of apical and effector caspases followed by cleavage of their nuclear substrates and morphological changes specific for apoptosis were observed in STS-treated cells. In contrast to treatment with radiation or chemotherapy drugs, STS induces mitochondrial dysfunction followed by translocation of AIF into the nuclei. These events preceded the activation of nuclear apoptosis. Thus, in lung carcinomas two cell death pathways, caspase-dependent and caspase-independent, coexist. In NSCLC cells, where the caspase-dependent pathway is less efficient, the triggering of an AIF-mediated caspase-independent mechanism circumvents the resistance of these cells to treatment.
AB - Apoptosis, a tightly controlled multi-step mechanism of cell death, is important for anti-cancer therapy-based elimination of tumor cells. However, this process is not always efficient. Small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) cells display different susceptibility to undergo apoptosis induced by anticancer treatment. In contrast to SCLC, NSCLC cells are cross-resistant to a broad spectrum of apoptotic stimuli, including receptor stimulation, cytotoxic drugs and γ-radiation. Since resistance of tumor cells to treatment often accounts for the failure of traditional forms of cancer therapy, in the present study attempts to find a potent broad-range apoptosis inductor, which can kill therapy-resistant NSCLC cells were undertaken and the mechanism of apoptosis induction by this drug was investigated in detail. We found that staurosporine (STS) had cell killing effect on both types of lung carcinomas. Release of cytochrome c, activation of apical and effector caspases followed by cleavage of their nuclear substrates and morphological changes specific for apoptosis were observed in STS-treated cells. In contrast to treatment with radiation or chemotherapy drugs, STS induces mitochondrial dysfunction followed by translocation of AIF into the nuclei. These events preceded the activation of nuclear apoptosis. Thus, in lung carcinomas two cell death pathways, caspase-dependent and caspase-independent, coexist. In NSCLC cells, where the caspase-dependent pathway is less efficient, the triggering of an AIF-mediated caspase-independent mechanism circumvents the resistance of these cells to treatment.
KW - AIF
KW - Apoptosis
KW - Caspases
KW - Lung cancer
KW - Staurosporine
UR - http://www.scopus.com/inward/record.url?scp=0037012040&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1205018
DO - 10.1038/sj.onc.1205018
M3 - Article
C2 - 11791177
AN - SCOPUS:0037012040
SN - 0950-9232
VL - 21
SP - 65
EP - 77
JO - Oncogene
JF - Oncogene
IS - 1
ER -