Free ISG15 triggers an antitumor immune response against breast cancer: a new perspective.
Interferon-Stimulated Gene 15 (ISG15), an antagonist of the canonical ubiquitin pathway, is frequently overexpressed in various cancers. In cancer cells, ISG15 is detected as free (intracellular) and conjugated to cellular proteins (ISGylation). Free ISG15 is also secreted into the extracellular milieu. ISGylation has protumor functions and extracellular free ISG15 has immunomodulatory properties in vitro. Therefore, whether ISG15 is a tumor suppressor or tumor promoter in vivo remains controversial. The current study aimed to clarify the role of free ISG15 in tumorigenesis. Breast cancer cells stably expressing control, ISG15, and UbcH8 (ISG15-specific E2 ligase) shRNAs were used to assess the immunoregulatory and antitumor function of free ISG15 in cell culture (in vitro) and in nude mice (in vivo). We show that extracellular free ISG15 suppresses breast tumor growth and increases NK cell infiltration into xenografted breast tumors in nude mice, and intracellular free ISG15 enhances major histocompatibility complex (MHC) class I surface expression in breast cancer cells. We conclude that free ISG15 may have antitumor and immunoregulatory function in vivo. These findings provides the basis for developing strategies to increase systemic levels of free ISG15 to treat cancer patients overexpressing the ISG15 pathway.
Department of Biochemistry & Molecular Biology, LSU Health Sciences Center-School of Medicine, New Orleans, LA, USA.|Present Address: Georgetown University Medical Center, Lombardi Comprehensive Cancer Center Department of Molecular Oncology, Washington, DC, USA.
Julian
J
Burks
Department of Biochemistry & Molecular Biology, LSU Health Sciences Center-School of Medicine, New Orleans, LA, USA.
Ryan E
RE
Reed
Department of Biochemistry & Molecular Biology, LSU Health Sciences Center-School of Medicine, New Orleans, LA, USA.
Shyamal D
SD
Desai
D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology* / Q000628:therapy; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007107:Immune System; D007694:Killer Cells, Natural / Q000166:cytology; D008285:Major Histocompatibility Complex; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D025801:Ubiquitin / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*
D016207:Cytokines; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D025801:Ubiquitin; D014452:Ubiquitins; C074034:ISG15 protein, human; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
ISG15; antitumor; breast cancer; immune system; ubiquitin/proteasome