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Mitochondrial dysfunction is an essential step for killing of non-small cell lung carcinomas resistant to
Bertrand Joseph1, Philippe Marchetti, Pierre Formstecher
1Institute of Environmental Medicine, Department of Toxicology, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden.
Abstract:
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 gamma-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.
Insights
Staurosporine effectively kills lung cancer cells by inducing apoptosis. It bypasses resistance in non-small cell lung carcinoma (NSCLC) by activating a caspase-independent cell death pathway.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Apoptosis is crucial for anti-cancer therapy, but cancer cells can develop resistance.
- Non-small cell lung carcinoma (NSCLC) exhibits cross-resistance to various apoptosis-inducing stimuli, limiting treatment efficacy.
Purpose of the Study:
- To identify a potent apoptosis inducer effective against therapy-resistant NSCLC cells.
- To investigate the detailed mechanism of apoptosis induction by staurosporine (STS) in lung carcinomas.
Main Methods:
- Treatment of SCLC and NSCLC cell lines with staurosporine (STS).
- Analysis of apoptosis markers including cytochrome c release, caspase activation, and morphological changes.
- Investigation of mitochondrial dysfunction and apoptosis-inducing factor (AIF) translocation.
Main Results:
- Staurosporine demonstrated a cell-killing effect on both SCLC and NSCLC cells.
- STS induced classical apoptosis markers, including caspase activation and nuclear substrate cleavage.
- STS triggered mitochondrial dysfunction and AIF translocation, preceding nuclear apoptosis, particularly in NSCLC cells.
Conclusions:
- Lung carcinomas possess both caspase-dependent and caspase-independent cell death pathways.
- Staurosporine effectively induces apoptosis in NSCLC by activating a caspase-independent pathway, circumventing treatment resistance.