Type I interferons (IFNs) are pleiotropic cytokines with important antineoplastic and antiviral activities and constitute key elements in the immune surveillance against cancer and viral infections. Although several interferon stimulated genes (ISGs) that mediate the antiviral properties of IFNs have been identified, very little is known on the genes and protein products that mediate generation of the antiproliferative and antineoplastic effects of IFNs. We have identified a novel family of ISGs, the family of SLFN genes. Our data have provided the first evidence that engagement of the Type I IFN receptor (IFNR) results in expression of mouse and human SLFN genes, and have demonstrated that members of this family are involved in the suppression of anchorage-independent malignant cell growth and inhibition of collagen invasion by melanoma cells. The current proposal is a systematic approach to define the roles of distinct SLFN genes in suppression of oncogenesis and in the generation of the antineoplastic effects of IFNs;and to examine whether defects in the expression of specific SLFNs correlates with IFN-resistance in vitro and in vivo.
Specific aim 1 will define the mechanisms of regulation of expression of SLFNs and will dissect the functional roles of distinct SLFNs in IFN-induced growth inhibitory effects. Studies to define effectors and mediators of responses downstream of SLFNs will be also performed.
Specific aim 2 will determine whether induction of expression of SLFN proteins is essential for generation of the antineoplastic effects of IFN? in solid tumor mouse models in vivo. For that purpose malignant melanoma or renal cell carcinoma (RCC) mouse models will be established using mice with the elektra phenotype (Slfn2eka/eka) or Slfn1 or Slfn3 knockout mice. Finally, specific aim 3 will examine whether defective expression of human SLFNs correlates with resistance to the antineoplastic properties of IFN1 on primary malignant cells from patients with malignant melanoma or renal cell carcinoma (RCC), malignancies known to be responsive to immune modulation and IFN-treatment. Altogether, the proposed studies will address important issues on the role of SLFNs in the generation of antitumor responses and the means by which malignant cells develop resistance to IFNs.

Public Health Relevance

Interferons (IFNs) play key roles in the immune surveillance against cancer and have important activities in certain clinical settings, but the precise mechanisms by which they generate their effects remain to be defined. We have identified a novel group of ISGs (SLFN genes) that regulate cell cycle progression and mediate IFN-dependent growth inhibitory responses. The current proposal will precisely define the role of these genes and their protein products in the generation of the antitumor properties of IFNs in vitro and in vivo. It will also determine whether defective expression of these genes correlates with resistance to the antitumor effects of IFNs against malignant melanoma and renal cell carcinoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA161796-02
Application #
8326070
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mccarthy, Susan A
Project Start
2011-09-01
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$316,438
Indirect Cost
$108,938
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Kroczynska, Barbara; Rafidi, Robert L; Majchrzak-Kita, Beata et al. (2016) Interferon ? (IFN?) Signaling via Mechanistic Target of Rapamycin Complex 2 (mTORC2) and Regulatory Effects in the Generation of Type II Interferon Biological Responses. J Biol Chem 291:2389-96
Iqbal, Asneha; Eckerdt, Frank; Bell, Jonathan et al. (2016) Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110? inhibition. Oncotarget 7:33192-201
Saleiro, Diana; Platanias, Leonidas C (2015) Intersection of mTOR and STAT signaling in immunity. Trends Immunol 36:21-9
Sassano, Antonella; Mavrommatis, Evangelos; Arslan, Ahmet Dirim et al. (2015) Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells. Mol Cell Biol 35:2684-98
Saleiro, Diana; Mehrotra, Swarna; Kroczynska, Barbara et al. (2015) Central role of ULK1 in type I interferon signaling. Cell Rep 11:605-17
Fish, Eleanor N; Platanias, Leonidas C (2014) Interferon receptor signaling in malignancy: a network of cellular pathways defining biological outcomes. Mol Cancer Res 12:1691-703
Kroczynska, Barbara; Mehrotra, Swarna; Arslan, Ahmet Dirim et al. (2014) Regulation of interferon-dependent mRNA translation of target genes. J Interferon Cytokine Res 34:289-96

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