Transcriptional program associated with IFN-alpha response of renal cell carcinoma.
Metastatic renal cell carcinoma (RCC) is refractory to therapy; however, 10%-20% of patients respond favorably with interferon-alpha (IFN-alpha) treatment. To understand the molecular basis of response to IFN-alpha therapy, we performed global gene expression analysis of sensitive and resistant RCC cell lines in the absence and in the presence of IFN-alpha, using high-density oligonucleotide arrays to detect differentially expressed genes. In the absence of IFN-alpha, no significant differences in gene expression were observed between six sensitive and six resistant cell lines. Gene expression analysis following a time course of IFN-alpha2b treatment in one sensitive (SK-RC-17) and one resistant (SK-RC-12) cell line revealed that 484 and 354 transcripts, respectively, were modulated. A considerable number of these transcripts were similarly modulated between the two cell types that included several known targets of IFN signaling associated with antiviral and immunomodulatory activity. A further analysis of gene expression pattern in response to IFN revealed that several transcripts associated with proapoptotic function were upregulated in the sensitive cells. In the resistant cells, transcripts associated with cell survival and proliferation were induced, and key apoptotic molecules were suppressed. This study suggests that the IFN-alpha response of individual RCC tumors is determined by the expression pattern of genes in the apoptosis vs. survival and proliferation pathways rather than by alterations in expression of one or more individual genes.
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Debendranath
D
Banerjee
Rajendrakumar S V
RS
Chadalavada
Veronique
V
Bourdon
James E
JE
Korkola
Robert J
RJ
Motzer
R S K
RS
Chaganti
D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D016898:Interferon-alpha / Q000494:pharmacology*; D007700:Kinetics; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects* / Q000276:immunology; D015854:Up-Regulation
D007155:Immunologic Factors; D016898:Interferon-alpha