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Consensus-interferon and platelet-derived growth factor adversely regulate proliferation and migration of Kaposi's
R Köster1, L M Blatt, M Streubert
1Abteilung Virusforschung, Max-Planck-Institut für Biochemie, Martinsried, Germany.
Abstract:
Platelet-derived growth factor-B (PDGF-B) is a potent paracrine-acting mitogen in Kaposi's sarcoma (KS) lesions. Interferon-alpha is widely used for clinical treatment of KS. Here we show that platelet-derived growth factor-B activates proliferation and migration of cultivated AIDS-KS spindle cells whereas interferon-alpha acts as an inhibitor. At the molecular level, these opposite activities of platelet-derived growth factor-B and interferon-alpha converged onto the adverse regulation of the c-myc gene expression. Platelet-derived growth factor-B induced c-myc mRNA and protein synthesis in cultivated AIDS-KS spindle cells whereas interferon-alpha inhibited these processes. Using c-myc-specific phoshothioate antisense oligodeoxynucleotides, we demonstrated that down-regulation of c-myc expression is sufficient to inhibit proliferation and migration of KS spindle cells in vitro. This indicated that c-Myc protein may be an important regulatory molecule of KS spindle cell proliferation and migration. High amounts of the c-Myc protein were detected in the nuclei of KS spindle cells in histological sections of AIDS-KS biopsies. This suggested that the c-myc gene may also regulate proliferation and migration of AIDS-KS spindle cells in vivo. In this case, c-myc may play an important role in the focus of major pathogenic and therapeutic pathways of KS.
Insights
Platelet-derived growth factor-B (PDGF-B) drives Kaposi's sarcoma (KS) cell growth, while interferon-alpha inhibits it. Targeting the c-myc gene, crucial for KS cell proliferation and migration, offers a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- Kaposi's sarcoma (KS) is a malignancy associated with Human Immunodeficiency Virus (HIV) infection.
- Platelet-derived growth factor-B (PDGF-B) acts as a mitogen in KS lesions.
- Interferon-alpha is a current clinical treatment for KS.
Purpose of the Study:
- To investigate the opposing roles of PDGF-B and interferon-alpha on AIDS-KS spindle cell proliferation and migration.
- To elucidate the molecular mechanisms underlying these effects, focusing on c-myc gene expression.
Main Methods:
- Cultivation of AIDS-KS spindle cells.
- Treatment with PDGF-B and interferon-alpha.
- Analysis of c-myc mRNA and protein expression.
- Use of c-myc-specific antisense oligodeoxynucleotides.
- Immunohistochemical analysis of KS biopsies.
Main Results:
- PDGF-B stimulated proliferation and migration of KS cells, while interferon-alpha inhibited these processes.
- Both PDGF-B and interferon-alpha modulated c-myc gene expression, with PDGF-B inducing and interferon-alpha suppressing it.
- Down-regulation of c-myc expression using antisense oligonucleotides inhibited KS cell proliferation and migration in vitro.
- High levels of c-Myc protein were observed in KS spindle cell nuclei in vivo.
Conclusions:
- c-Myc protein is a key regulator of KS spindle cell proliferation and migration.
- The c-myc gene plays a significant role in the pathogenesis and potential therapeutic targeting of KS.