P53 in malignant glioma: 20 years later and still much to learn

Abstract

p53, as a key and common mutagenic target in the development of malignant glioma, was initially brought to the attention of the neuro-oncology community more than 20 years ago (Nature 1989;342:705–708). As of March 3, 2010, a PubMed search for articles containing glioma and p53 in the title or abstract yielded 1647 hits. Clearly, p53 has and continues to hold our interest as we persevere to understand its many roles in glioma development and biology. Due to the numerous cellular processes that are directly or indirectly influenced by p53 function, it often seems that the more we learn about p53, the more we appreciate how much remains to be learned. The incompleteness of our understanding is suggested in the titles of two articles published in the current (Geng et al1) and April (Kim et al2) issues of Neuro-Oncology. It is noteworthy that these two studies, conducted independently by teams of investigators in different countries and continents, each address GBM's response to the quinoline derivative chloroquine, and each approaches GBM's chloroquine response from a p53 perspective. However, the conclusions of these studies are surprisingly distinct, as indicated by their titles. In the former (Kim et al2), established GBM cell lines were tested, in the presence and absence of endogenous p53 knockdown, for their apoptotic response to chloroquine. GBM cells expressing wild-type p53 underwent decreased chloroquine-induced apoptosis when treated in a p53-depleted state. In the latter investigation, for which some of the same cell lines were used as in the former study and in which cell lines were treated with chloroquine at similar concentrations, the opposite was concluded: that cellular p53 status was not a key determinant of chloroquine-induced cell death. These distinct conclusions may be associated with the time frames of the experiments: the former involving an analysis of effects over periods as long as 7 days and showing a time-dependent increase in the extent of chloriquine anti-tumor activity in GBM with wild-type vs. mutant p53 and the latter involving an analysis of chloroquine's effects at a single time point: 1 day. Potentially, the combined results of these reports indicate that short-term, p53-independent chloroquine anti-tumor effects exist through influence on autophagic response (Geng et al1), whereas long-term cellular response to treatment with chloroquine is p53 dependent through influence on caspase-mediated apoptosis. Regardless of whether this or alternative hypotheses help explain the basis for the different interpretations of GBM p53 status and response to chloroquine, these studies share a common theme of being p53 centric with respect to interpretation and serve to highlight our continuing fascination with this tumor suppressor gene and its protein product.