HONG KONG – The discovery of cancer-associated functions of a ligase enzyme and the gene encoding for it by researchers from Singapore, China and the U.S. may lead to the development of a new approach to the treatment of glioma.

Comprising approximately 30 percent of all brain and central nervous system tumors and 80 percent of all brain malignancies, gliomas are associated with an age-adjusted mortality rate of 4.25 per 100,000 per population per year in the U.S. Depending on the results of an initial biopsy and taking into account tumor location, symptoms and potential benefits vs. risks of the different modalities, glioma treatment may include observation, surgery, radiation therapy or chemotherapy.

However, even with aggressive treatment using surgery, radiation and chemotherapy, the median reported survival is still less than one year, although the oral alkylating agent, temozolomide, has shown promise in malignant gliomas and other difficult-to-treat tumors.

PARK2, also known as PARKIN, is an E3 ubiquitin ligase enzyme encoded by the PARK2 gene. While the exact function of PARK2 is not known, it is involved with protein degradation, and PARK2 gene mutations are known to cause a familial form of Parkinsonism.

In addition, PARK2 dysfunction has been associated with the progression of Parkinson's disease and certain human malignancies, although its role in cancer remains to be explored more fully.

"PARK2 has been associated with the progression of almost all kinds of solid tumors, including gastric, lung, breast and cervical cancer, melanoma and pancreatic adenocarcinoma," said corresponding study author Dong Yin.

In the April 15, 2015, issue of Cancer Research, researchers led by H. Phillip Koeffler, the Mark Goodson chair professor of oncology research in the Division of Hematology/Oncology at Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, reported that the PARK2 gene was frequently deleted and underexpressed in human glioma, and that low PARK2 expression was associated with poor survival.

"The PARK2 gene has a deletion in about 20 percent of gliomas, and low expression is associated with poor survival in glioma patients," said Yin, who is a researcher at the Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

Moreover, the restoration of PARK2 activity was shown to significantly inhibit glioma cell growth both in vitro and in vivo, whereas depletion of PARK2 promoted cell proliferation. "The cells with overexpression of PARK2 grew slowly in vitro and formed smaller tumors in vivo," noted Yin.

The collaboration of researchers, which also included those from Cancer Science Institute of Singapore and elsewhere in China and the U.S., also demonstrated that PARK2 attenuated both Wnt- and EGF-stimulated intracellular signaling pathways through down-regulation of the intracellular level of beta-catenin and epidermal growth factor receptor (EGFR).

The Wnt and EGFR pathways play key roles in embryonic development and cell proliferation, with dysregulation of those pathways being known to lead to tumorigenesis, including breast and prostate cancers and gliomas.

"The Wtn and EGFR signaling pathways are two well-known pathways for stimulating cancer cell growth, inducing cell differentiation and maintenance of undifferentiated cell status," Yin explained.

Mutations and overexpression of the protein beta-catenin, which is involved with regulation of cell-cell adhesion and gene transcription, also are associated with multiple cancers, including hepatocellular and colorectal carcinomas and lung cancer.

Notably, the researchers found that PARK2 physically interacted with both beta-catenin and EGFR, and they further discovered that PARK2 promoted ubiquitination of those two proteins in an E3 ligase activity-dependent manner.

SMALL-MOLECULE INHIBITORS

Those newly identified tumor-suppressive functions of PARK2 inspired the researchers to test and demonstrate that a combination of small-molecule inhibitors targeting both the Wnt–beta-catenin and EGFR–AKT signaling pathways synergistically impaired glioma cell viability.

"When treated with a combination of these two small molecular inhibitors, [glioma] cell growth was slower compared with either of the two molecules alone," Yin told BioWorld Today.

"Because low PARK2 expression causes activation of the Wnt and EGFR pathways, then those two pathways could be targeted in glioma patients with low or mutant PARK2," he added.

"Together, our findings uncover novel cancer-associated functions of PARK2 and provide a potential therapeutic approach to treat glioma," concluded Yin, adding that in the future, the researchers will "study the molecular mechanisms whereby PARK2 regulates EGFR." //