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Interferon-alpha and -gamma inhibit the growth and neoplastic potential of v-src-transformed human epithelial cells
H Fujishima1, S Nakano, T Tatsumoto
1First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka City, Japan.
Abstract:
To investigate whether interferons (IFNs) selectively suppress the growth of solid tumor cells with elevated protein tyrosine kinase (PTK) activity, we evaluated the effect of recombinant IFN-alpha2a and IFN-gamma on the proliferative and neoplastic potentials triggered by p60v-src using v-src-transformed HAG-1 human epithelial cells. When compared with control cells harboring the pSV2neo gene, the monolayer growth of v-src-transformed cell lines was inhibited by both recombinant IFNs, in a dose-dependent manner, whereas growth of ras-transfected cell lines was not affected. Moreover, IFNs markedly reduced the clonogenic growth of v-src-transformed cells in soft-agar rather than monolayer growth, suggesting the preferential activity of IFNs on anchorage-independent growth. Pretreatment of cells with Src or the Src-like PTK inhibitor herbimycin A or radicicol, alleviated dose-dependently the growth-inhibitory activity of IFN-alpha2a against v-src-transformed cells, suggesting that IFNs may share a common inhibitory pathway with Src PTK inhibitors. Accordingly, like herbimycin A, IFNs were found to reduce tyrosine phosphorylation of p60v-src and suppressed in vitro p60v-src kinase activity in v-src-transformed cells. Our data, together with the fact that IFNs inhibit the growth potential driven by Src but not by activated Ras, suggest that inhibition of signal transduction pathway through Src to downstream transduction events may be a primary mechanism of IFN-induced anti-prolifeative and anti-tumoral activity.
Insights
Interferons (IFNs) selectively inhibit solid tumor cell growth driven by elevated protein tyrosine kinase (PTK) activity, specifically targeting Src signaling pathways. This suggests IFNs may offer a targeted anti-cancer therapy by interfering with key tumor growth mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Solid tumors often exhibit elevated protein tyrosine kinase (PTK) activity, driving uncontrolled proliferation.
- Interferons (IFNs) are known immunomodulatory cytokines with potential anti-tumor effects.
- The specific mechanisms by which IFNs suppress tumor growth, particularly in relation to PTK activity, require further elucidation.
Purpose of the Study:
- To investigate the selective inhibitory effects of interferons (IFNs) on solid tumor cells with elevated protein tyrosine kinase (PTK) activity.
- To determine if IFNs preferentially suppress growth driven by Src, a specific PTK, compared to other signaling pathways like Ras.
- To explore the potential shared inhibitory pathways between IFNs and PTK inhibitors.
Main Methods:
- Utilized v-src-transformed HAG-1 human epithelial cells and ras-transfected cell lines to assess IFN effects.
- Administered recombinant IFN-alpha2a and IFN-gamma, observing impacts on monolayer and soft-agar colony formation.
- Employed Src PTK inhibitors (herbimycin A, radicicol) to investigate pathway interactions with IFNs.
- Measured tyrosine phosphorylation of p60v-src and in vitro kinase activity.
Main Results:
- Both IFN-alpha2a and IFN-gamma dose-dependently inhibited monolayer growth of v-src-transformed cells, but not ras-transfected cells.
- IFNs preferentially reduced clonogenic growth in soft-agar, indicating preferential activity against anchorage-independent growth.
- IFN treatment alleviated Src PTK inhibitor effects and reduced p60v-src tyrosine phosphorylation and kinase activity.
- IFNs inhibited Src-driven growth but not Ras-driven growth.
Conclusions:
- Interferons selectively suppress solid tumor cell growth associated with elevated Src PTK activity.
- IFNs appear to share common inhibitory pathways with Src PTK inhibitors, targeting tyrosine phosphorylation and kinase activity.
- Inhibition of the Src signal transduction pathway may represent a primary mechanism for IFN-induced anti-proliferative and anti-tumoral effects.