IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression.
We reported previously that 23% of human lung adenocarcinoma cell lines were unresponsive to IFN-gamma. To extend this finding to cancer cells derived from distinct tissues of origin, we assessed IFN-gamma receptor signaling in the LNCaP human prostate adenocarcinoma cell line, which in previous experiments by others failed to induce a range of IFN-dependent biological responses. In this report, we show that LNCaP cells fail to respond to either IFN-gamma or IFN-alpha because of an impairment in the proximal signaling events downstream of both IFN-gamma and IFN-alpha/beta receptors that lead to the activation of STAT1. Furthermore, we show that LNCaP insensitivity to the IFNs is a result of the absence of expression of the JAK1 kinase, an obligate component shared by both IFN-gamma and IFN-alpha/beta receptors. JAK1 was undetectable in LNCaP cells at both protein and message levels. Treatment of LNCaP cells with a combination of inhibitors of DNA methyltransferases and histone deacetylases induced expression of JAK1 message. These results identify the molecular basis for IFN insensitivity in the LNCaP cell line and suggest that epigenetic silencing of key immunologic signaling components may be one mechanism by which tumor cells evade immune detection and elimination.
Dunn
Gavin P
GP
Department of Pathology and Immunology, Center for Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Sheehan
Kathleen C F
KC
Old
Lloyd J
LJ
Schreiber
Robert D
RD
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D016898:Interferon-alpha; D007371:Interferon-gamma / Q000494:pharmacology*; D053613:Janus Kinase 1; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D011994:Recombinant Proteins; D015398:Signal Transduction; D014162:Transfection
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007370:Interferon Type I; D016898:Interferon-alpha; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C080665:interferon-alpha A-D; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1