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Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

Oncogene volume 18, pages 7514–7526 (1999)Cite this article

Abstract

While 25% of human cancers harbor oncogenic Ras mutations, such mutations are not found in astrocytomas. We have previously demonstrated that the activation of receptor tyrosine kinases expressed by malignant human astrocytoma cells and specimens results in functional upregulation of the Ras signalling pathway and increased levels of activated Ras•GTP. Farnesyl transferase inhibitors (FTIs) are promising anti-cancer agents in early clinical trials, which may exert their effect through pharmacological inhibition of the Ras signalling pathway. In this study we establish the anti-tumorigenic properties of the FTI L-744,832 against a panel of malignant human astrocytoma cell lines. Furthermore, we demonstrate the multiple mechanisms by which L-744,832 exerts its effect. L-744,832 demonstrates both cytostatic and cytotoxic effects on astrocytoma cells, and cells expressing a truncated constitutively phosphorylated Epidermal Growth Factor Receptor common in high-grade astrocytomas (EGFRvIII/p140EGF-R) demonstrate increased sensitivity to the agent. L-744,832 is capable of inducing apoptosis in astrocytoma cells under anchorage-dependent conditions; this process occurs in a p53-independent manner and is associated with increased expression of Bax and Bak. L-744,832 also induces cell cycle arrest at both the G1/M and G2/S checkpoints; this process is also independent of p53 mutational status. Cell cycle arrest in drug-treated cells can be accompanied by induction of p21WAF1/CIP1, but this induction is not necessary for the cell cycle inhibitory effects, nor is it dependent on functional p53. Finally, angiogenesis in astrocytomas has been shown to be dependent on secretion of Vascular Endothelial Growth Factor (VEGF) by tumour cells, particularly under hypoxic conditions. L-744,832 potently inhibits the secretion of VEGF under hypoxic conditions. These combinations of mechanisms suggest that these tumours, despite the absence of oncogenic Ras mutations, will be amenable to growth inhibition by FTIs, through a combination of anti-proliferative, pro-apoptotic, and anti-angiogenic effects.

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Acknowledgements

The authors wish to acknowledge the help of Janusz Rak and Robert Kerbel in the design of experiments assessing the secretion of VEGF by these cells. Allen Oliff (Merck Research Laboratories) provided the farnesyl transferase inhibitor L-744,832. FACS analysis was carried out with the help of Juliet Shannon in the FACS facility at the Princess Margaret Hospital/Ontario Cancer Institute. Immunocytochemistry was performed with assistance from Luba Roncari. Northen blotting for VEGF mRNA was performed by Hao Ding and Xiaoli Wu. This study was supported by an operating grant from the National Cancer Institute of Canada (NCIC). MM Feldkamp is supported by a Research Fellowship of the NCIC, provided in part by funds from the Terry Fox Run. A Guha is supported by a Clinician Scientist Award from the Medical Research Council of Canada.

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Authors and Affiliations

  1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    Matthias M Feldkamp, Nelson Lau & Abhijit Guha

  2. Division of Neurosurgery, Toronto Western Hospital, University Health Network and University of Toronto, Toronto, Ontario, Canada

    Matthias M Feldkamp & Abhijit Guha

  3. Department of Surgical Oncology, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada

    Abhijit Guha

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Feldkamp, M., Lau, N. & Guha, A. Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects. Oncogene 18, 7514–7526 (1999). https://doi.org/10.1038/sj.onc.1203105

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