Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of Bcl-X _L and caspase-3-like proteases

Abstract

Alterations of the epidermal growth factor receptor (EGFR) gene occur frequently in human malignant gliomas. The most common of these is deletion of exons 2-7, resulting in truncation of the extracellular domain (⌬EGFR or EGFRvIII), which occurs in a large fraction of de novo malignant gliomas (but not in progressive tumors or those lacking p53 function) and enhances tumorigenicity, in part by decreasing apoptosis through up-regulation of Bcl-X L . Here, we demonstrate that the ⌬EGFR concomitantly confers resistance to the chemotherapeutic drug cisplatin (CDDP) by suppression of CDDP-induced apoptosis. Expression of Bcl-X L was elevated in U87MG.⌬EGFR cells prior to and during CDDP treatment, whereas it decreased considerably in CDDP-treated parental cells. CDDP-induced activation of caspase-3-like proteases was suppressed significantly in U87MG.⌬EGFR cells. These responses were highly specific to constitutively kinase-active ⌬EGFR, because overexpression of kinase-deficient ⌬EGFR (DK) or wild-type EGFR had no such effects. Correspondingly, ⌬EGFR specific tyrosine kinase inhibitors reduced Bcl-X L expression and potentiated CDDP-induced apoptosis in U87MG.⌬EGFR cells. Ectopic overexpression of Bcl-X L in parental U87MG cells also resulted in suppression of both caspase activation and apoptosis induced by CDDP. These results may have important clinical implications for the use of CDDP in the treatment of those malignant gliomas expressing ⌬EGFR.

Regulation of PUMA-α by p53 in cisplatin-induced renal cell apoptosis

“…With cisplatin, the culture-associated Bcl-xL expression is diminished. Similar observations have been documented in cancerous cells (Nagane et al, 1998;Akeshima et al, 2001). Although the mechanism underlying the suppression is unknown, it may be related to changes in cell cycle.…”

Dynamics of chemosensitivity and chromosomal instability in recurrent glioblastoma

“…In a previous study, we observed correlation between MVP expression of glioblastoma cells and resistance to anthracyclines (Berger et al, 2001), which suggests a contribution of MVP at least to doxorubicin hypersensitivity of BTL3 cells. Additionally, EGFR-transmitted signals are known to contribute to apoptosis resistance of glioblastoma cells (Shinojima et al, 2003) leading, for example, to CDDP insensitivity (Nagane et al, 1998). Moreover, response of xenografted gliomas to different alkylating agents was attenuated by EGFR amplification (Leuraud et al, 2004).…”

ROS, stress‐activated kinases and stress signaling in cancer

“…For example, non-small-cell lung carcinoma cells become more resistant to cytotoxic agents such as cisplatin, doxorubicin and etoposide as the level of Her-2/neu expression is elevated, but upon blockage of Her-2/neu signaling the cells become re-sensitized to these agents (Tsai et al, 1996). Similarly, the overexpression of a mutated EGFR in advanced glioma correlates with resistance to cisplatin due to reduced apoptosis, and blocking EGFR signaling in these cells restores their cisplatin sensitivity (Nagane et al, 1998). Blocking Her-2 with Herceptin (Trastuzumab) sensitizes highly drug-resistant breast cancer cells to cytotoxic drugs (Pegram et al, 2000).…”