CD95‐mediated Apoptosis of Human Glioma Cells: Modulation by Epidermal Growth Factor Receptor Activity

Abstract

The death ligands CD95L and Apo2L/TRAIL are promising investigational agents for the treatment of malignant glioma. EGFR is overexpressed in a significant proportion of malignant gliomas in vivo. Here, we report that CD95L-induced cell death is enhanced by EGFR inhibition using tyrphostine AG1478 in 7 of 12 human malignant glioma cell lines. Conversely, CD95-mediated and Apo2L-induced cell death are both inhibited by overexpression of EGFR in LN-229 cells. CD95L-induced cell death augmented by AG1478 is accompanied by enhanced processing of caspase 8. LN-229 cells overexpressing the viral caspase inhibitor, crm-A, are not sensitized to CD95L-induced cell death by AG1478, indicating that EGFR exerts its antiapoptotic properties through a caspase 8-dependent pathway. These data define a modulatory effect of EGFR-activity on death ligand-induced apoptosis and indicate that EGFR inhibition is likely to improve the efficacy of death ligand-based cancer therapies. Furthermore, it is tempting to speculate that EGFR amplification protects tumor cells from death ligand-mediated host immune responses in vivo and that EGFR's effects on death receptor-mediated apoptosis may explain the anti-tumor effects of non-cytotoxic, unarmed anti-EGFR family antibodies.

Inhibition of Epidermal Growth Factor Receptor Signaling Protects Human Malignant Glioma Cells from Hypoxia-Induced Cell Death

“…Under normoxic conditions, EGFR signaling may enhance proliferation, invasion, and migration of glioma cells (5). Furthermore, EGFR signaling has antiapoptotic properties (6 -8), e.g., the pharmacological inhibition of EGFR sensitizes human malignant glioma cells to death ligand-induced apoptosis (9). Effects of EGFR on proliferation and survival are thought to be mediated by the mitogen-activated protein kinase (MAPK) and PI3K/ Akt pathways, respectively (7,8,10).…”

The role of HRK gene in human cancer

“…Analyses of apoptosis and proliferation provide much clinically useful information for tumor development, prognosis and treatment response (Nakamura et al, 1997). Some limited studies have focused on critical regulators of apoptosis (Steinbach et al, 2002;Debatin et al, 2003), and high apoptotic counts have been associated with high histological grade and shortened survival . Activated regulation of mitogen-activated protein kinases and Fas-associated death domain-containing proteins affects cell growth, proliferation, survival and progression in prostate cancers .…”

“…Various studies have been performed investigating the genetic factors related to prostate carcinogenesis (Konishi et al, 2005a(Konishi et al, , b, 2008, but as yet, critical specific molecular markers that clearly identify malignant potential have not been found. Apoptosis regulators play one of the most critical roles in tumorigenesis, and an imbalance between cell proliferation and apoptosis contributes to tumor progression (Steinbach et al, 2002;Debatin et al, 2003). Analyses of apoptosis and proliferation provide much clinically useful information for tumor development, prognosis and treatment response (Nakamura et al, 1997).…”

“…Its deregulation, together with defective control of proliferation, contributes to critical tumor progression (Evan and Vousden, 2001;Steinbach et al, 2002;Debatin et al, 2003). Analyses of cell turnover relating to apoptosis and proliferation provide insights into tumor doubling time, prognosis and treatment response (Zhang et al, 1998) in that high apoptotic counts have been associated with a high histological grade and shortened survival in a number of studies (Vakkala et al, 1999).…”

HRK inactivation associated with promoter methylation and LOH in prostate cancer

“…An imbalance between cell proliferation and apoptosis may contribute to tumor progression and some recent studies have focused on critical regulators of apoptosis [3,4]. Analyses of cell turnover relating to apoptosis and proliferation provide insights into tumor doubling time, prognosis, and treatment response [5] in that, in limited studies, high apoptotic counts have been associated with high histological grade and shortened survival [6].…”