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Parkin pathway activation mitigates glioma cell proliferation and predicts patient survival

ABSTRACT: Mutations in the parkin gene, which encodes a ubiquitin ligase, are a major genetic cause of parkinsonism. Interestingly, parkin also plays a role in cancer as a putative tumor suppressor, and the gene is frequently targeted by deletion and inactivation in human malignant tumors. Here, we investigated a potential tumor suppressor role for parkin in gliomas. We found that parkin expression was dramatically reduced in glioma cells. Restoration of parkin expression promoted G1 phase cell cycle arrest and mitigated the proliferation rate of glioma cells in vitro and in vivo. Notably, parkin-expressing glioma cells showed a reduction in levels of cyclin D1, but not cyclin E, and a selective downregulation of Akt serine-473 phosphorylation and VEGF receptor levels. In accordance, cells derived from a parkin null mouse model exhibited increased levels of cyclin D1, VEGF receptor and Akt phosphorylation and divided significantly faster when compared with wild type cells, with suppressionof these changes following parkin re-introduction. Clinically, analysis of parkin pathway activation was predictive for the survival outcome of glioma patients. Taken together, our study provides mechanistic insight into the tumor suppressor function of parkin in brain tumors, and suggests that measurement of parkin pathway activation may be used clinically as a prognostic tool in brain tumor patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE29494 | GEO | 2012/03/15

SECONDARY ACCESSION(S): PRJNA141657

REPOSITORIES: GEO

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Project description:Mutations in the parkin gene, which encodes a ubiquitin ligase, are a major cause of autosomal recessive parkinsonism. Interestingly, parkin also plays a role in cancer as a putative tumor suppressor. Consistent with this, the gene is frequently targeted by deletion and inactivation in human malignant tumors. Here, we show that parkin expression is dramatically reduced in glioma cells, which correlates with increased cancer mortality. We further show that restoration of parkin expression in these cells promotes their arrest at G1 phase and significantly mitigates their proliferation rate both in vitro and in vivo. Notably, the level of cyclin D1, but not cyclin E, is reduced in parkin-expressing glioma cells. Moreover, parkin expression also leads to a selective downregulation of Akt serine-473 phosphorylation and VEGF receptor levels. Supporting this, cells derived from parkin null mouse exhibit increased levels of cyclin D1, VEGF receptor and Akt phosphorylation and divide significantly faster compared to their wild type counterparts. Importantly, analysis of parkin pathway activation revealed its predictive power for survival outcome of glioma patients. Taken together, our study provides a mechanism by which parkin exerts its tumor suppressor function and a signature pathway of parkin that is of potential prognostic value. Total RNA obtained from U-87MG cells stably expressing parkin or vector alone. Replicate arrays were performed for each of the 3 vector and parkin-expressing U-87MG clones.

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