Transcriptional response of T cells to IFN-alpha: changes induced in IFN-alpha-sensitive and resistant cutaneous T cell lymphoma.
Interferon-alpha (IFN-alpha) therapy is commonly used in the treatment of neoplastic and autoimmune diseases, including cutaneous T cell lymphoma (CTCL). However, the IFN-alpha response is unpredictable, and the IFN-alpha cell targets and pathways are only partially understood. To delineate the molecular mechanisms of IFN-alpha activity, gene expression profiling was performed in a time-course experiment of both IFN-alpha sensitive and IFN-alpha-resistant variants of a CTCL cell line. These experiments revealed that IFN-alpha is responsible for the regulation of hundreds of genes in both variants and predominantly involves genes implicated in signal transduction, cell cycle control, apoptosis, and transcription regulation. Specifically, the IFN-alpha response of tumoral T cells is due to a combination of induction of apoptosis in which TNFSF10 and HSXIAPAF1 may play an important role and cell cycle arrest achieved by downregulation of CDK4 and CCNG2 and upregulation of CDKN2C and tumor suppressor genes (TSGs). Resistance to IFN-alpha appears to be associated with failure to induce IRF1 and IRF7 and deregulation of the apoptotic signals of HSXIAPAF1, TRADD, BAD, and BNIP3. Additionally, cell cycle progression is heralded by upregulation of CDC25A and CDC42. A critical role of NF-kappaB in promoting cell survival in IFN-alpha-resistant cells is indicated by the upregulation of RELB and LTB.
Tracey
Lorraine
L
Molecular Pathology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
Spiteri
Inmaculada
I
Ortiz
Pablo
P
Lawler
Mark
M
Piris
Miguel A
MA
Villuendas
Raquel
R
D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000276:immunology*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015533:Transcriptional Activation
D016898:Interferon-alpha