GENOMIC AND FUNCTIONAL ANALYSIS OF THE E3 LIGASE PARK2 IN GLIOMA

Abstract

PARK2 (PARKIN) IS AN E3 UBIQUITIN LIGASE WHOSE DYSFUNCTION HAS BEEN ASSOCIATED WITH THE PROGRESSION OF PARKINSONISM AND HUMAN MALIGNANCIES. HOWEVER, THE ROLE OF PARK2 IN CANCER REMAINS TO BE EXPLORED. THIS STUDY REPORTS THAT PARK2 IS FREQUENTLY DELETED AND UNDER-EXPRESSED IN GLIOMA, AND LOW PARK2 EXPRESSION IS ASSOCIATED WITH POOR SURVIVAL. RESTORATION OF PARK2 SIGNIFICANTLY INHIBITED GLIOBLASTOMA CELL GROWTH, WHILE DEPLETION OF PARK2 PROMOTED CELL PROLIFERATION. FURTHERMORE, PARK2 ATTENUATED BOTH WNT3A- AND EGF-STIMULATED PATHWAYS THROUGH DOWN-REGULATING THE INTRACELLULAR LEVEL OF ?-CATENIN AND EGFR. NOTABLY, PARK2 PHYSICALLY INTERACTED WITH BOTH ?-CATENIN AND EGFR, AND PROMOTED THEIR UBIQUITINATION. THE GROWTH RETARDATION CAUSED BY ECTOPIC PARK2 WAS FULLY OR PARTIALLY RESCUED BY EITHER ?-CATENIN OVEREXPRESSION OR EGF SUPPLEMENT. FINALLY, COMBINATION OF SMALL-MOLECULE INHIBITORS TARGETING BOTH WNT-?-CATENIN AND EGFR-AKT PATHWAYS SYNERGISTICALLY INHIBITED GLIOBLASTOMA GROWTH. T