Current chemotherapy of malignant tumors of the central nervous system rarely results in significant long-term responses. Two major factors underlying this poor therapeutic outcome are the intrinsic resistance of brain tumors to chemotherapy and the poor selectivity and high toxicity of current treatments. The development of more tumor-specific therapies and therapeutic strategies for brain tumors, however, will require knowledge of the molecular mechanisms and abnormalities that drive the growth and therapeutic response of the tumors. This project is built on recent findings in our laboratory on the crosstalk between a major Phase II drug metabolizing and cell signaling protein, the glutathione S-transferase P1 (GSTP1) and the serine/threonine protein kinase, PKC. These two proteins are highly expressed in many human tumors, including, those of the brain and the high expression has been associated with rapid progression and failure of chemotherapy in several of these malignancies. In gliomas, high GSTP1 expression and its nuclear localization have been associated with poor patient survival. Similarly, high PKC activity is frequently observed in malignant gliomas and has been associated with glioma drug resistance. Recently, we reported that the GSTP1 protein is a, heretofore, unrecognized downstream target of PKC and undergoes phosphorylation by PKC, resulting in a significant enhancement of its metabolic activity. Our preliminary data suggest that these two pathways can function interactively to increase the resistance of glioma cells to anticancer agents. Our goal in this application is to investigate these seminal findings for their prognostic significance and as a basis for developing more effective therapy for malignant gliomas. The hypothesis to be tested is that phosphorylation of the GSTP1 protein by the PKC family of serine/threonine kinases, will enhance the ability of the GSTP1 protein to metabolize and inactivate chemotherapeutic agents and to inhibit downstream jun N-terminal kinase signaling, thus, leading to more aggressive growth and increased drug resistance of gliomas. We postulate that PKC inhibition/downregulation, alone and/or in combination with GSTP1 downregulation, will have significant antiglioma efficacy and increase glioma sensitivity to chemotherapy. The proposed research will provide important insights into the cellular pathways mediated by this newly identified crosstalk between GSTP1 and PKC in gliomas and the role that this interaction plays in tumor growth and therapeutic response in gliomas. The results are likely to lead to novel therapeutic strategies for malignant gliomas, particularly those characterized by high GSTP1 expression and elevated or highly activated PKCs. Malignant gliomas are among the most therapeutically intractable tumors. In this application, we propose research to better characterize a newly identified crosstalk between two proteins, glutathione S-transferase P1 (GSTP1) a major Phase II drug metabolizing and cell signaling protein, and the serine/threonine protein kinase, PKC, in which the latter phosphorylates and increases the catalytic activity of the former. Both proteins are highly expressed in malignant gliomas and are associated with rapid progression and failure of chemotherapy.
We characterize the phosphorylation of GSTP1 by PKC and examine how the modulation of the phosphorylation alters the drug sensitivity of gliomas in vitro and in vivo. The results are likely to lead to novel therapeutic strategies for malignant gliomas, particularly;those characterized by high GSTP1 expression and elevated or highly activated PKCs.
