Raf inhibitor stabilizes receptor for the type I interferon but inhibits its anti-proliferative effects in human malignant melanoma cells

Interferon alpha (IFNα) 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 βTrcp E3 ubiquitin ligase) and IFNα signaling were reduced in 1205Lu melanoma cell line that harbors activated BRAF and exhibits high levels of βTrcp 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 βTrcp and stabilized IFNAR1. However, despite causing stabilization of IFNAR1, Raf inhibitor BAY 43-9006 interfered with cellular responses to IFNα 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 IFNα in melanoma patients.

[1]  M. Herlyn,et al.  Oncogenic BRAF regulates β-Trcp expression and NF-κB activity in human melanoma cells , 2007, Oncogene.

[2]  J. Soria,et al.  Phase I Trial of Sorafenib in Combination with IFN α-2a in Patients with Unresectable and/or Metastatic Renal Cell Carcinoma or Malignant Melanoma , 2007, Clinical Cancer Research.

[3]  J. Sosman,et al.  Molecular Targets in Melanoma from Angiogenesis to Apoptosis , 2006, Clinical Cancer Research.

[4]  D. Hedley,et al.  Raf kinase as a target for anticancer therapeutics , 2005, Molecular Cancer Therapeutics.

[5]  D. Tuveson,et al.  Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. , 2005, Cancer research.

[6]  S. Fuchs,et al.  Phosphorylation and Specific Ubiquitin Acceptor Sites Are Required for Ubiquitination and Degradation of the IFNAR1 Subunit of Type I Interferon Receptor* , 2004, Journal of Biological Chemistry.

[7]  S. Fuchs,et al.  The many faces of β-TrCP E3 ubiquitin ligases: reflections in the magic mirror of cancer , 2004, Oncogene.

[8]  S. Fuchs,et al.  SCFHOS ubiquitin ligase mediates the ligand‐induced down‐regulation of the interferon‐α receptor , 2003 .

[9]  D. Tuveson,et al.  Suppression of BRAF(V599E) in human melanoma abrogates transformation. , 2003, Cancer research.

[10]  D. Jelinek,et al.  Atypical expression of ErbB3 in myeloma cells: cross-talk between ErbB3 and the interferon-α signaling complex , 2003, Oncogene.

[11]  V. Sondak,et al.  Malignant melanoma: current state of primary and adjuvant treatment. , 2003, Critical reviews in oncology/hematology.

[12]  J. Grob,et al.  Cost-effectiveness of interferon-α2 as adjuvant therapy in malignant melanoma , 2003 .

[13]  D. Elder,et al.  Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. , 2003, Cancer research.

[14]  A. Eggermont.  Critical appraisal of IFN-α-based adjuvant therapy in Stage II–III malignant melanoma , 2002 .

[15]  F. Romerio,et al.  MEK and ERK inhibitors enhance the antiproliferative effect of interferon‐α2b , 2002 .

[16]  T. Slaga,et al.  Induction of Homologue of Slimb Ubiquitin Ligase Receptor by Mitogen Signaling* , 2002, The Journal of Biological Chemistry.

[17]  T. Slaga,et al.  Inhibition of HOS expression and activities by Wnt pathway , 2002, Oncogene.

[18]  P. Duray,et al.  Neonatal sunburn and melanoma in mice , 2001, Nature.

[19]  T. Taniguchi,et al.  A weak signal for strong responses: interferon-alpha/beta revisited , 2001, Nature Reviews Molecular Cell Biology.

[20]  F. Fagnani,et al.  Economic analysis of adjuvant therapy with interferon alpha-2a in stage II malignant melanoma. , 2001, European journal of cancer.

[21]  V. Soldatenkov,et al.  Inhibition of homologue of Slimb (HOS) function sensitizes human melanoma cells for apoptosis. , 1999, Cancer research.

[22]  A. Abbruzzese,et al.  Interferon-α induces apoptosis in human KB cells through a stress-dependent mitogen activated protein kinase pathway that is antagonized by epidermal growth factor , 1999, Cell Death and Differentiation.

[23]  G. Stark,et al.  How cells respond to interferons. , 1998, Annual review of biochemistry.

[24]  M. Tymms,et al.  A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  C. Samuel,et al.  Ligand-independent anti-oncogenic activity of the alpha subunit of the type I interferon receptor. , 1994, The Journal of biological chemistry.

[26]  M Aguet,et al.  Functional role of type I and type II interferons in antiviral defense. , 1994, Science.

[27]  S. Constantinescu,et al.  Complementation of the interferon alpha response in resistant cells by expression of the cloned subunit of the interferon alpha receptor. A central role of this subunit in interferon alpha signaling. , 1994, The Journal of biological chemistry.

[28]  M. Herlyn,et al.  Oncogenic BRAF regulates beta-Trcp expression and NF-kappaB activity in human melanoma cells. , 2007, Oncogene.

[29]  S. Fuchs,et al.  SCF(HOS) ubiquitin ligase mediates the ligand-induced down-regulation of the interferon-alpha receptor. , 2003, The EMBO journal.

[30]  J. Grob,et al.  Cost-effectiveness of interferon-alpha2 as adjuvant therapy in malignant melanoma. , 2003, Expert opinion on pharmacotherapy.

[31]  A. Eggermont.  Critical appraisal of IFN-alpha-based adjuvant therapy in stage II-III malignant melanoma. , 2002, Expert review of anticancer therapy.

[32]  F. Romerio,et al.  MEK and ERK inhibitors enhance the anti-proliferative effect of interferon-alpha2b. , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  Y. Xiong,et al.  HOS, a human homolog of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IkappaB and beta-catenin. , 1999, Oncogene.

[34]  A. Abbruzzese,et al.  Interferon-alpha induces apoptosis in human KB cells through a stress-dependent mitogen activated protein kinase pathway that is antagonized by epidermal growth factor. , 1999, Cell death and differentiation.

[35]  L. A. Goldman,et al.  Characterization of antihuman IFNAR-1 monoclonal antibodies: epitope localization and functional analysis. , 1999, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.