Raf inhibitor stabilizes receptor for the type I interferon but inhibits its anti-proliferative effects in human malignant melanoma cells.
Interferon alpha (IFNalpha) is widely used in treatment of malignant melanoma patients. This cytokine acts on cells by engaging Type I IFN receptor consisting of two subunits, (IFNAR1 and IFNAR2) followed by activation of Janus kinases (Jak). Levels of IFNAR1 (regulated via degradation mediated by the betaTrcp E3 ubiquitin ligase) and IFNalpha signaling were reduced in 1205Lu melanoma cell line that harbors activated BRAF and exhibits high levels of betaTrcp ubiquitin ligase. Expression of stabilized IFNAR1 in melanoma cells decreased their tumorigenicity. Furthermore, RNAi-mediated BRAF knockdown and pharmacologic inhibition of either Raf or MEK1 decreased levels of betaTrcp and stabilized IFNAR1. However, despite causing stabilization of IFNAR1, Raf inhibitor BAY 43-9006 interfered with cellular responses to IFNalpha most likely due to its ability to directly inhibit Jak activity. We discuss the implications of this result for combination therapy with BAY 43-9006 and IFNalpha in melanoma patients.
Kumar
K G Suresh
KG
Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Liu
Jianghuai
J
Li
Ying
Y
Yu
Duonan
D
Thomas-Tikhonenko
Andrei
A
Herlyn
Meenhard
M
Fuchs
Serge Y
SY
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*
D016207:Cytokines; D007370:Interferon Type I; D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf