Abstract
Poor prognosis and resistance to therapy in malignant gliomas is mainly due to the highly dispersive nature of glioma cells. This dispersive characteristic results from genetic alterations in key regulators of cell migration and diffusion. A better understanding of these regulatory signals holds promise to improve overall survival and response to therapy. Using mapping arrays to screen for genomic alterations in gliomas, we recently identified alterations of the protein tyrosine phosphatase receptor type kappa gene (PTPRK) that correlate to patient outcomes. These PTPRK alterations are very relevant to glioma biology as PTPRK can directly sense cell–cell contact and is a dephosphorylation regulator of tyrosine phosphorylation signaling, which is a major driving force behind tumor development and progression. Subsequent sequencing of the full length PTPRK transcripts revealed novel PTPRK gene deletion and missense mutations in numerous glioma biopsies. PTPRK mutations were cloned and expressed in PTPRK-null malignant glioma cells. The effect of these mutations on PTPRK anti-oncogenic function and their association with response to anti-glioma therapeutics, such as temozolomide and tyrosine kinase inhibitors, was subsequently analyzed using in vitro cell-based assays. These genetic variations altered PTPRK activity and its post-translational processing. Reconstitution of wild-type PTPRK in malignant glioma cell lines suppressed cell growth and migration by inhibiting EGFR and β-catenin signaling and improved the effect of conventional therapies for glioma. However, PTPRK mutations abrogated tumor suppressive effects of wild-type PTPRK and altered sensitivity of glioma cells to chemotherapy.
Highlights
Patients with malignant glioma have a poor prognosis due to the widespread infiltration of tumor cells into surrounding healthy brain parenchyma, hyper-vascularization and drug resistance
We discovered that alterations of the phosphatase receptor type kappa gene (PTPRK) gene were among the most significant abnormalities
These results suggest that PTPRK negatively regulate epidermal growth factor receptor (EGFR) and b-catenin expression likely resulting from a decrease in tyrosine phosphorylation of EGFR and b-catenin which has been previously reported in other cancer types [17,25,26,27]
Summary
Patients with malignant glioma have a poor prognosis due to the widespread infiltration of tumor cells into surrounding healthy brain parenchyma, hyper-vascularization and drug resistance. One of the frequently altered regulatory signals in glioma is constitutive protein tyrosine phosphorylation (TP) that drives cell growth and migration [4,5]. Targeting the TP regulatory signals represents a potential therapeutic approach and is important given the fact that the preliminary efficacy results of most clinical trials, targeting tyrosine kinase activity, have fallen short of expectations [3,7]. Recent studies suggest a key role of protein tyrosine phosphatases (PTPs) mediated dephosphorylation in reducing TP levels in cancer cells [4,8]. Functional effects of alterations in PTPs’ dephosphorylating activity have been recently reported in human tumors [8,9], no single PTP study has as yet shown to influence the malignant phenotype and drug response in glioma
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