Post-surgical recurrence or development of metastatic disease in patients with malignant melanoma is associated with a very high level of mortality. Unfortunately, the efficacy of adjuvant therapy with recombinant interferon alpha (IFN1) is limited by the development of strategies that allow the tumor to evade the anti- proliferative and anti-angiogenic effects of IFN1. Such strategies are likely acquired early in melanoma development/progression to circumvent the anti-tumorigenic effects of endogenous IFN1. Our laboratory made the seminal discovery that phosphorylation-dependent degradation of the IFNAR1 subunit of IFN1 receptor is a key mechanism by which the sensitivity to IFN1 is regulated. Moreover, preliminary data reveal that melanoma cells can accelerate IFNAR1 degradation and inhibit IFN1 signaling by secreting inflammatory cytokines such as interleukin 1 (IL1). These cytokines induce the specific IFNAR1 phosphorylation that leads to recruitment of the ?Trcp E3 ubiquitin ligase and subsequent ubiquitination and degradation of IFNAR1. Activation of p38 kinase appears to play a central role in the degradation of IFNAR1 via this pathway. Importantly, p38 kinase activation and IFNAR1 phosphorylation/downregulation also occur in normal melanocytes in response to ultraviolet light (UV), implicated in the etiology of malignant melanoma. Together, these data have led us to hypothesize that development and progression of malignant melanoma is abetted by UV and/or inflammatory cytokine-induced p38 kinase-dependent degradation of IFNAR1. The consequent reduction in IFN1/2 sensitivity would allow tumor cells to evade the anti-proliferative and pro- apoptotic effects of IFN1/2. To test this hypothesis, we will: (i) determine whether inflammatory cytokines regulate the sensitivity of malignant melanomas to IFN1 therapy by inducing p38-mediated degradation of IFNAR1, and evaluate the role of accelerated IFNAR1 degradation in malignant melanoma development (ii) and progression (iii). Multiple complementary in vitro and in vivo approaches will be utilized, including unique mouse models, melanomas expressing IFNAR1 variants that are resistant to this degradation pathway, and comprehensive panels of human melanoma cell lines and clinical samples. We anticipate that these studies will highlight an important role for UV-induced and/or inflammation-mediated degradation of IFNAR1 in melanoma etiology and pathogenesis, thereby revealing novel aspects of melanomagenesis that could be targeted for early intervention. Moreover, these studies will investigate the molecular mechanisms underlying the resistance of established melanoma to therapeutic IFN1, thereby providing essential insight for the development of novel targets for increasing the therapeutic efficacy of IFN1.

Public Health Relevance

Malignant melanoma is a lethal disease. Melanoma growth and progression are restricted by effects of endogenous cytokine IFN1 which acts via IFNAR1 receptor. Therapy using recombinant IFN1 is often effective against melanoma but eventually melanoma cells become insensitive. Here we investigate the mechanisms utilized by melanoma cells to degrade the receptor and escape from IFN1 control. Completion of this study is expected to identify novel targets for future development of potent means to improve the outcome of melanoma treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092900-12
Application #
8508860
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Hildesheim, Jeffrey
Project Start
2001-03-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
12
Fiscal Year
2013
Total Cost
$239,401
Indirect Cost
$54,547
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chowdhury, A Roy; Long, A; Fuchs, S Y et al. (2017) Mitochondrial stress-induced p53 attenuates HIF-1? activity by physical association and enhanced ubiquitination. Oncogene 36:397-409
Katlinski, Kanstantsin V; Gui, Jun; Katlinskaya, Yuliya V et al. (2017) Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment. Cancer Cell 31:194-207
Ortiz, Angélica; Fuchs, Serge Y (2017) Anti-metastatic functions of type 1 interferons: Foundation for the adjuvant therapy of cancer. Cytokine 89:4-11
Davar, Diwakar; Fuchs, Serge Y; Kirkwood, John M (2016) BRAF Inhibitors and IFN?: Plus, Minus, or Indeterminate? J Natl Cancer Inst 108:
Katlinskaya, Yuliya V; Katlinski, Kanstantsin V; Yu, Qiujing et al. (2016) Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression. Cell Rep 15:171-80
Xia, Chuan; Vijayan, Madhuvanthi; Pritzl, Curtis J et al. (2016) Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1. J Virol 90:2403-17
Katlinskaya, Yuliya V; Katlinski, Kanstantsin V; Lasri, Audrey et al. (2016) Type I Interferons Control Proliferation and Function of the Intestinal Epithelium. Mol Cell Biol 36:1124-35
Pytel, Dariusz; Gao, Yan; Mackiewicz, Katarzyna et al. (2016) PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma. PLoS Genet 12:e1006518
Zhang, Kang-Jian; Yin, Xiao-Fei; Yang, Yuan-Qin et al. (2016) A Potent In Vivo Antitumor Efficacy of Novel Recombinant Type I Interferon. Clin Cancer Res :
Xu, Zhenhua; Bu, Yiwen; Chitnis, Nilesh et al. (2016) miR-216b regulation of c-Jun mediates GADD153/CHOP-dependent apoptosis. Nat Commun 7:11422

Showing the most recent 10 out of 65 publications