Tamoxifen Induces Cytotoxic Autophagy in Glioblastoma
Christopher D Graham1, Niroop Kaza1, Barbara J Klocke1
1From the Department of Pathology (CDG, NK, BJK, LAS, SLC, KAR); and Department of Neurosurgery, University of Alabama at Birmingham (GYG), Birmingham, Alabama.
Abstract:
Glioblastomas (GBMs) are the most common and aggressive primary human malignant brain tumors. 4-Hydroxy tamoxifen (OHT) is an active metabolite of the tamoxifen (TMX) prodrug and a well-established estrogen receptor (ER) and estrogen-related receptor antagonist. A recent study from our laboratory demonstrated that OHT induced ER-independent malignant peripheral nerve sheath tumor (MPNST) cell death by autophagic degradation of the prosurvival protein Kirsten rat sarcoma viral oncogene homolog. Because both MPNST and GBM are glial in cell origin, we hypothesized that OHT could mediate similar effects in GBM. OHT induced a concentration-dependent reduction in cell viability that was largely independent of caspase activation in a human GBM cell line and 2 patient-derived xenolines. Further, OHT induced both cytotoxic autophagy and a concentration-dependent decrease in epidermal growth factor receptor (EGFR) protein levels. A GBM cell line expressing EGFR variant III (EGFRvIII) was relatively resistant to OHT-induced death and EGFRvIII was refractory to OHT-induced degradation. Thus, OHT induces GBM cell death through a caspase-independent, autophagy-related mechanism and should be considered as a potential therapeutic agent in patients with GBM whose tumors express wild-type EGFR.
Insights
4-Hydroxy tamoxifen (OHT) effectively reduces glioblastoma (GBM) cell viability through a novel mechanism involving autophagy, not caspase activation. This suggests OHT as a potential therapeutic for GBM with wild-type epidermal growth factor receptor.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastomas (GBMs) are aggressive primary brain tumors.
- 4-Hydroxy tamoxifen (OHT), an active tamoxifen metabolite, is an estrogen receptor antagonist.
- OHT previously demonstrated efficacy in inducing cell death in malignant peripheral nerve sheath tumors (MPNSTs) via autophagy.
Purpose of the Study:
- To investigate the efficacy of OHT in glioblastoma (GBM) treatment.
- To elucidate the mechanism of OHT-induced cell death in GBM.
- To determine the role of epidermal growth factor receptor (EGFR) in OHT's action.
Main Methods:
- Treatment of human GBM cell lines and patient-derived xenolines with varying concentrations of OHT.
- Assessment of cell viability and caspase activation.
- Analysis of autophagic markers and EGFR protein levels.
- Evaluation of OHT effects on GBM cells expressing wild-type EGFR versus EGFR variant III (EGFRvIII).
Main Results:
- OHT induced a concentration-dependent reduction in GBM cell viability, largely independent of caspase activation.
- OHT triggered cytotoxic autophagy and decreased EGFR protein levels in a concentration-dependent manner.
- GBM cells expressing EGFRvIII exhibited resistance to OHT-induced cell death and EGFRvIII degradation.
Conclusions:
- OHT induces glioblastoma cell death via a caspase-independent, autophagy-related mechanism.
- The degradation of wild-type EGFR appears to be involved in OHT's cytotoxic effect.
- OHT warrants consideration as a potential therapeutic agent for GBM patients with wild-type EGFR tumors.
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