Abstract
Abstract PARK2 is an E3 ubiquitin ligase whose dysfunction has been associated with the progression of autosomal recessive juvenile Parkinson's disease and human malignancies. However, its role in cancer remains to be explored. In this study, we report that PARK2 is frequently deleted and underexpressed in human glioma, and low PARK2 expression is associated with poor survival in cohorts of both low-grade glioma and glioblastoma multiforme (GBM). Functional studies revealed a tumor-suppressive role of PARK2 in GBM cells. Restoration of PARK2 significantly inhibited glioma cell growth both in vitro and in vivo, while depletion of endogenous PARK2 promoted cell proliferation. cDNA microarray analysis showed that PARK2 expression strongly altered the activity of both the Wnt and EGFR pathways. Immunoblot analysis confirmed that ectopic expression of PARK2 suppressed the intracellular levels of β-catenin, EGFR, as well as their down-stream targets including Cyclin D1, TCF4, c-Myc, p-AKT and p-S6K, etc. Notably, PARK2 physically interacted with both β-catenin and EGFR, and promoted their ubiquitination in an E3-ligase dependent manner. Similar to the ligase-dead PARK2 mutant (C431S), three PARK2 mutants harboring cancer-derived somatic mutations (T173A, T240M and P294S) showed decreased ability to ubiquitinate either β-catenin or EGFR proteins. We further found that PARK2 attenuated the cellular response to both Wnt3a and EGF stimulation, suggesting PARK2 is a negative regulator of both the Wnt and EGFR pathways. Lastly, inspired by these newly identified functions of PARK2, we tested and proved that the combination of small-molecule inhibitors targeting both Wnt-β-catenin and EGFR-AKT pathways synergistically impaired glioma cell viability. In aggregate, our findings uncover novel, cancer-associated functions of PARK2 and provide a potential therapeutic approach to treat glioma. Citation Format: Liang Xu, De-Chen Lin, Ye Chen, Haiyan Yan, Masaharu Hazawa, Ngan Doan, Jonathan W. Said, Ling-Wen Ding, Li-Zhen Liu, Henry Yang, Shi-zhu Yu, Michael Kahn, Dong Yin, Phillip Koeffler. PARK2 is a negative regulator of Wnt and EGFR pathways in glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 122. doi:10.1158/1538-7445.AM2015-122
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