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J Invest Dermatol. 2015 Mar;135(3):861-868. doi: 10.1038/jid.2014.364. Epub 2014 Aug 14.

c-CBL E3 ubiquitin ligase is overexpressed in cutaneous T-cell lymphoma: its inhibition promotes activation-induced cell death.

Author information

1
Department of Dermatology, University of Wisconsin and the Middleton VA Medical Center, Madison, Wisconsin, USA.
2
Department of Dermatology, University of Wisconsin and the Middleton VA Medical Center, Madison, Wisconsin, USA. Electronic address: gwood@dermatology.wisc.edu.

Abstract

Mycosis fungoides and Sézary syndrome are two major forms of cutaneous T-cell lymphoma (CTCL) characterized by resistance to apoptosis. A central pathway for T-cell apoptosis is activation-induced cell death, which is triggered through the T-cell receptor (TCR). This results in upregulation of FAS ligand (FASL) and subsequent apoptosis through the FAS death receptor pathway. It has been known for more than a decade that TCR signaling is defective in CTCL; however, the underlying mechanism has not been apparent. In this report, we show that the E3 ubiquitin ligase, c-CBL, is overexpressed in CTCL and that its knockdown overcomes defective TCR signaling, resulting in phosphorylation of PLC-g1, calcium influx, ROS generation, upregulation of FASL, and extrinsic pathway apoptosis in CTCL cells expressing adequate FAS. In CTCL cells with suboptimal FAS expression, FAS can be upregulated epigenetically by derepression of the FAS promoter using methotrexate, which we showed previously has activity as a DNA methylation inhibitor. Using these combined strategies, FAS-low as well as FAS-high CTCL cells can be killed effectively.

PMID:
25140833
PMCID:
PMC4324119
DOI:
10.1038/jid.2014.364
[Indexed for MEDLINE]
Free PMC Article

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