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 G 1 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 suppression of these changes following parkin reintroduction. Clinically, analysis of parkin pathway activation was predictive for the survival outcome of patients with glioma. 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 patients with brain tumor. Cancer Res; 72(10); 2543-53. Ó2012 AACR.

Inactivation of parkin by promoter methylation correlated with lymph node metastasis and genomic instability in nasopharyngeal carcinoma

“…14,15 Parkin acts as a master regulator of the stability of G1/S cyclins by regulating cyclin-cyclin-dependent kinase complexes. [16][17][18] Parkin expression induces the cell division cycle 2 (CDC2) protein phosphorylation, which inhibits CDC2 activity and causes G2/M cell cycle arrest in tumor necrosis factor (TNF)-α-treated HeLa cells. 19 Parkin serves as a tumor suppressor in human cervical cancer cells resistant to TNF-α-induced cell death by modulating survivin expression and caspase activity.…”

Embelin-induced brain glioma cell apoptosis and cell cycle arrest via the mitochondrial pathway

“…Brain glioma has become the focus of research on diseases of the central nervous system due to its high incidence and poor treatment outcome (3,4). At present, brain glioma is mainly treated with surgery, radiotherapy and chemotherapy, but the curative effect and prognosis are far from optimistic particularly for tumors of higher pathological grade.…”

Progenitor-like Traits Contribute to Patient Survival and Prognosis in Oligodendroglial Tumors

“…Since then, the Connectivity Map has been successfully used to determine the degree of oncogenic pathway activation in gastric cancer (23). We also recently showed that such a method supported the mechanistic role of Parkin as a tumor suppressor in glioma (24). We show that this oligodendroglial gene signature is a positive prognostic factor in gliomas and detects heterogeneity in oligodendroglial tumor patient survival profiles that cannot be predicted by the 1p/19q codeletion status alone.…”