Overexpression of protein kinase C epsilon in astroglial brain tumor derived cell lines and primary tumor samples.

Abstract

Prognosis for astroglial brain tumors that are not amenable to surgical resection remains poor. Consequently, a need to identify new cellular targets and chemotherapeutics for the treatment of astroglial tumors remains. Important reports indicate that human astroglial cell lines express higher protein kinase C (PKC) activity in comparison to normal astrocytes. PKC designates a family of kinases that regulate many cellular functions including cell growth and differentiation. The tight regulation of PKC activity is crucial for maintaining normal cellular proliferation since excessive activity leads to uncontrolled growth and cellular transformation. PKCepsilon, one of the 11 known PKC isozymes, has been shown to function as an oncogene in rodent fibroblasts by enhancing c-Raf-1 kinase activity leading to the stimulation of mitogen-activated protein (MAP) kinase pathway. We recently demonstrated that the ability of substance P (SP) neuropeptide to activate MAP kinase pathway in U-373MG astrocytoma cells correlates with its ability to selectively translocate PKCepsilon from cytosolic to membrane fraction, and that PKC inhibitors (e.g. CGP 41251) inhibit the activation of this pathway by SP or the PKC activator 12-O-tetradecanoyl phorbol 13-acetate (TPA). In this study, we demonstrated that PKCepsilon is overexpressed in many astroglial cell lines (n=27 lines), thus providing new evidence as to the possible involvement of this isozyme in the pathology of astroglial tumors. Consistently, we demonstrated that PKCepsilon is overexpressed in primary pediatric anaplastic astrocytoma (grade III) tumor samples as well as in cell lines derived from them, and that glioblastoma multiforme (grade IV) and gliosarcoma tumor samples, but not pilocytic astrocytomas (grade I), also express high levels of PKCepsilon. Therefore, the reported increase in PKC activity in brain tumor derived cell lines may be, in part, attributed to the overexpression of PKCepsilon and possibly other PKC isozymes. Consequently, we propose that the use of PKCepsilon selective inhibitors may be beneficial in the treatment of astroglial brain tumors.