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Mol Cell. 2018 Nov 1;72(3):413-425.e5. doi: 10.1016/j.molcel.2018.08.040. Epub 2018 Oct 4.

The Proto-oncogene c-Kit Inhibits Tumor Growth by Behaving as a Dependence Receptor.

Author information

1
Apoptosis, Cancer and Development Laboratory - Equipe labellisée "La Ligue," LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, 69008 Lyon, France.
2
Apoptosis, Cancer and Development Laboratory - Equipe labellisée "La Ligue," LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, 69008 Lyon, France; Netris Pharma, 69008 Lyon, France.
3
Apoptosis, Cancer and Development Laboratory - Equipe labellisée "La Ligue," LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, 69008 Lyon, France. Electronic address: andrea.paradisi@lyon.unicancer.fr.
4
Apoptosis, Cancer and Development Laboratory - Equipe labellisée "La Ligue," LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, 69008 Lyon, France; Netris Pharma, 69008 Lyon, France; Department of Translational Research and Innovation, Centre Léon Bérard, 69008 Lyon, France. Electronic address: patrick.mehlen@lyon.unicancer.fr.

Abstract

c-Kit is a classic proto-oncogene either mutated or upregulated in cancer cells, and this leads to its constitutive kinase activation and, thus, to uncontrolled proliferation. Although the pro-oncogenic role of c-Kit is of no doubt, some observations do not fit well with c-Kit solely as a tumor-promoting moiety. We show here that c-Kit actively triggers cell death in various cancer cell lines unless engaged by its ligand stem cell factor (SCF). This pro-death activity is enhanced when the kinase activation of c-Kit is silenced and is due to c-Kit intracellular cleavage by caspase-like protease at D816. Moreover, in vivo, overexpression of a c-Kit kinase-dead mutant inhibits tumor growth, and this intrinsic c-Kit tumor-suppressive activity is dependent on the D816 cleavage. Thus, c-Kit acts both as a proto-oncogene via its kinase activity and as a tumor suppressor via its dependence receptor activity.

KEYWORDS:

SCF; apoptosis; c-Kit; cancer; caspase; dependence receptors; receptor tyrosine kinase

PMID:
30293784
DOI:
10.1016/j.molcel.2018.08.040
[Indexed for MEDLINE]

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