Investigating the cell death mechanism(s) of 4-hydroxy-tamoxifen in glioblastoma (411.1)

Tamoxifen (TMX) is widely used as a chemotherapeutic agent in the treatment of estrogen receptor (ER)-positive breast cancer. Recent studies have demonstrated that TMX inhibits the growth of malignant peripheral nerve sheath tumors (MPNSTs) through an ER-independent mechanism associated with the induction of autophagy. We hypothesize that TMX could induce autophagic cell death in glioblastoma (GBM), the most common and aggressive malignant astrocytic glioma. In an established human GBM cell line and xenografts, TMX caused a concentration-dependent decrease in cell viability that was not mediated by caspase 3-like enzymatic activity. We observed a concentration-dependent decrease in KRAS protein levels and an accumulation of LC3-II, a surrogate marker of autophagic vacuoles. Finally, because epidermal growth factor receptor (EGFR) amplification is frequently associated with GBM and elevated EGFR signaling is known to contribute to the malignant properties of GBM, we examined the effects of TMX on EGFR and ...