Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells.
Cancer cells are thought to possess mechanisms for evading the host's immune surveillance system. Survivin, a member of the inhibitor-of-apoptosis family overexpressed by cancer cells, inhibits Fas-mediated apoptosis induced by immune cells. In addition, cancer cells express Fas ligand (FasL) on their surfaces as a counterattack against immune cells. Mechanisms by which cancer cells express FasL, including involvement of survivin, are unclear. In the present study, we demonstrated that survivin up-regulated FasL expression and investigated how this might occur. Quantitative immunostaining showed correlation between survivin and FasL protein expression in colon cancer tissues (r=0.79). FasL expression was up-regulated in LS180 colon cancer cells transfected with the survivin gene. Transfectants showed increased cytotoxicity against a Fas-sensitive human T leukemia cell line, Jurkat. In contrast, FasL expression was down-regulated in SW480 cells transfected with a small inhibitory RNA to prevent survivin expression. Survivin gene transfectants showed increased DNA binding of transcription factor specificity protein 1 (Sp1) to the FasL promoter, and up-regulation of Sp1 phosphorylation at serine and threonine residues; the total amount of Sp1 was unchanged. Thus, survivin enables cancer cells not only to suppress immune cell attack by inhibiting Fas-mediated apoptotic signaling, but to attack immune cells by induction of FasL.
Department of Clinical Laboratory Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan.
Koichi
K
Asanuma
Naoki
N
Tsuji
Teruo
T
Endoh
Atsuhito
A
Yagihashi
Naoki
N
Watanabe
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D019169:Jurkat Cells; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000276:immunology; D016329:Sp1 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D000077022:Survivin; D014158:Transcription, Genetic / Q000276:immunology; D014162:Transfection; D015854:Up-Regulation / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism
D000276:Adjuvants, Immunologic; C107489:BIRC5 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016329:Sp1 Transcription Factor; D000077022:Survivin; D019014:fas Receptor