Interleukin-29 binds to melanoma cells inducing Jak-STAT signal transduction and apoptosis

• Published in: Molecular cancer therapeutics 2010-02, Vol.9 (2), p.510-520
• Main Authors: Guenterberg, Kristan D, Grignol, Valerie P, Raig, Ene T, Zimmerer, Jason M, Chan, Anthony N, Blaskovits, Farriss M, Young, Gregory S, Nuovo, Gerard J, Mundy, Bethany L, Lesinski, Gregory B, Carson, 3rd, William E
• Format: Article
• Language: English
• Subjects: Apoptosis; Boronic Acids - pharmacology; Bortezomib; Cell Line, Tumor; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Gene Expression Regulation, Neoplastic; Humans; Interferons; Interleukins - metabolism; Janus Kinase 1 - metabolism; Melanoma - metabolism; Oligonucleotide Array Sequence Analysis; Phosphorylation; Pyrazines - pharmacology; Signal Transduction; Skin Neoplasms - metabolism; STAT Transcription Factors - metabolism; Temozolomide
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-09-0461

Interleukin-29 (IL-29) is a member of the type III IFN family that has been shown to have antiviral activity and to inhibit cell growth. Melanoma cell lines were tested for expression of the IL-29 receptor (IL-29R) and their response to IL-29. Expression of IL-28R1 and IL-10R2, components of IL-29R, was evaluated using reverse transcription-PCR. A combination of immunoblot analysis and flow cytometry was used to evaluate IL-29-induced signal transduction. U133 Plus 2.0 Arrays and real-time PCR were used to evaluate gene expression. Apoptosis was measured using Annexin V/propridium iodide staining. In situ PCR for IL-29R was done on paraffin-embedded melanoma tumors. Both IL-28R1 and IL-10R2 were expressed on the A375, 1106 MEL, Hs294T, 18105 MEL, MEL 39, SK MEL 5, and F01 cell lines. Incubation of melanoma cell lines with IL-29 (10-1,000 ng/mL) led to phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2. Microarray analysis and quantitative reverse transcription-PCR showed a marked increase in transcripts of IFN-regulated genes after treatment with IL-29. In the F01 cell line, bortezomib-induced and temozolomide-induced apoptosis was synergistically enhanced following the addition of IL-29. In situ PCR revealed that IL-10R2 and IL-28R1 were present in six of eight primary human melanoma tumors but not in benign nevi specimens. In conclusion, IL-29 receptors are expressed on the surface of human melanoma cell lines and patient samples, and treatment of these cell lines with IL-29 leads to signaling via the Jak-STAT pathway, the transcription of a unique set of genes, and apoptosis.