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K252a inhibits proliferation of glioma cells by blocking platelet-derived growth factor signal transduction
L S Chin1, S F Murray, K M Zitnay
1Department of Neurosurgery, Program in Oncology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. lchin@surgery1.ab.umd.edu
Abstract:
Growth factors are known to regulate glioma proliferation. The glioma cell lines U87 and T98G were examined for evidence of an autocrine stimulatory loop involving the neurotrophin family of growth factors. Although neurotrophin-3 and TrkC RNA were detected by reverse transcription-PCR, there was no evidence of significant interaction between neurotrophin-3 and its cognate receptor TrkC. The microbial alkaloid K252a has been described to inhibit both Trk tyrosine kinase activity and neuroblastoma cell proliferation. K252a inhibited proliferation in U87 (IC50 = 1170 nM) and T98G (IC50 = 529 nM) but induced apoptosis in U87 cells only. At concentrations of 500 nM to 1 microM, K252a blocked only platelet-derived growth factor (PDGF)-mediated receptor autophosphorylation. These results suggest that an autocrine loop involving PDGF is functional and important for maintaining tumor growth. There is no evidence to support the existence of a neurotrophin-mediated autocrine loop. K252a, through inhibition of PDGF signal transduction, may be a novel therapeutic agent in the treatment of human gliomas.
Insights
This study investigated growth factor loops in glioma cells. Results indicate platelet-derived growth factor (PDGF) drives tumor growth, suggesting K252a as a potential therapeutic agent for gliomas.
Area of Science:
- Neuroscience
- Oncology
- Molecular Biology
Background:
- Growth factors significantly influence glioma cell proliferation.
- Autocrine stimulatory loops are implicated in tumor growth.
- Neurotrophins and their receptors play roles in cellular regulation.
Purpose of the Study:
- To investigate the presence of autocrine stimulatory loops involving neurotrophins in U87 and T98G glioma cell lines.
- To evaluate the effect of the microbial alkaloid K252a on glioma cell proliferation and signaling pathways.
- To determine the potential of K252a as a therapeutic agent for human gliomas.
Main Methods:
- Reverse transcription-polymerase chain reaction (RT-PCR) to detect RNA for neurotrophin-3 and TrkC.
- Cell proliferation assays to determine the IC50 of K252a in U87 and T98G cells.
- Western blotting to assess the effect of K252a on platelet-derived growth factor (PDGF)-mediated receptor autophosphorylation.
Main Results:
- Neurotrophin-3 and TrkC RNA were detected, but no significant interaction was observed.
- K252a inhibited proliferation in U87 (IC50 = 1170 nM) and T98G (IC50 = 529 nM) glioma cells.
- K252a induced apoptosis in U87 cells and blocked PDGF-mediated receptor autophosphorylation at specific concentrations.
- Evidence supports a functional autocrine loop involving PDGF in glioma growth, but not neurotrophins.
Conclusions:
- A neurotrophin-mediated autocrine loop is not evident in these glioma models.
- An autocrine loop involving PDGF is functional and crucial for glioma tumor growth.
- K252a demonstrates potential as a novel therapeutic agent for human gliomas by inhibiting PDGF signal transduction.