Mitochondrial dysfunction is an essential step for killing of non-small cell lung carcinomas resistant to conventional treatment

被引：47

作者：

Joseph B. ^{[1
,5
]}

Marchetti P. ^{[2
]}

Formstecher P. ^{[2
]}

Kroemer G. ^{[3
]}

Lewensohn R. ^{[4
]}

Zhivotovsky B. ^{[1
]}

机构：

[1] Institute of Environmental Medicine, Department of Toxicology, Karolinska Institutet, S-171 77 Stockholm

[2] Institut National de la Santé et de la Recherche Médicale U459, Faculté de Médecine, Lille Cedex

[3] Centre National de la Recherche Scientifique, CNRS-ULR1599, Institut Gustave Roussy, 94805 Villejuif

[4] Unit of Medical Radiobiology, Cancer Center Karolinska, Karolinska Institutet

[5] Ludwig Institute for Cancer Research, Karolinska Institutet, S-171 77 Stockholm

来源：

Oncogene | 2002年 / 21卷 / 1期

关键词：

AIF; Apoptosis; Caspases; Lung cancer; Staurosporine;

D O I：

10.1038/sj.onc.1205018

中图分类号：

学科分类号：

摘要：

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.

引用

页码：65 / 77

页数：12

共 37 条

[11]

Gescher A., Crit. Rev. Oncol/Hematol, 34, pp. 127-135, (2000)

[12]

Han Z., Pantazis P., Lange T.S., Wyche J.H., Hendrickson E.A., Cell Death Diff, 7, pp. 521-530, (2000)

[13]

Hengartner M., Nature, 407, pp. 770-776, (2000)

[14]

Jarvis W.D., Grant S., Invest. New Drugs, 17, pp. 227-240, (1999)

[15]

Johnson V.L., Ko S.C., Holmstrom T.H., Eriksson J.E., Chow S.C., J. Cell Sci, 113, pp. 2941-2953, (2000)

[16]

Josa N., Susin S.A., Daugas E., Stanford W.L., Cho S.K., Li C.Y., Sasaki T., Elia A.J., Cheng H.Y., Ravagnan L., Ferri K.F., Zamzami N., Wakeham A., Hakem R., Yoshida H., Kong Y.Y., Mak T.W., Zuniga-Pflucker J.C., Kroemer G., Penninger J.M., Nature, 410, pp. 549-554, (2001)

[17]

Joseph B., Ekedahl J., Sirzen F., Lewensohn R., Zhivotovsky B., Biochem. Biophys. Res. Commun, 262, pp. 381-387, (1999)

[18]

Joseph B., Ekedahl J., Lewensohn R., Marchetti P., Formstecher P., Zhivotovsky B., Oncogene, 20, pp. 2877-2888, (2001)

[19]

Joseph B., Lewensohn R., Zhivotovsky B., Ann. NY. Acad. Sci, 926, pp. 204-216, (2000)

[20]

Kluck R., Bossy-Wetzel E., Green D., Newmeyer D., Science, 275, pp. 1132-1136, (1997)

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