Abstract 5190: The proto-oncogene Proline Glutamic acid Leucine rich Protein1 (PELP1) is a novel mediator of glioblastoma development.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Glioblastomas (GBM) are the most common and aggressive tumors of the central nervous system and still remains as one of the deadliest human cancers. Despite tremendous improvement in the standard therapies, the survival of glioblastoma patients is approximately 12-14 months. The development of novel molecular targets and effective therapeutics are urgently needed to curb the progression of GBM. Better understanding of the molecular pathways and mechanisms that contributes to the GBM development is clinically significant and will provide novel therapeutic targets. In the present study, we examined the significance of proto-oncogene PELP1 that functions as a coregulator of many nuclear transcriptional factors. PELP1 expression is common deregulated in hormonal cancers, however, less is known about PELP1 signaling and its significance in glioma progression. Utilizing immunohistochemical analysis of glioma tissue microarrays that contain different grades of astrocytomas, oligodendrogliomas, ependymomas and normal brain tissues, we found that PELP1 is overexpressed in the glial tumors compared to normal brain, with highest expression in GBM, and PELP1 expression levels were positively correlated with histological malignancy. PELP1 expression was also found to be elevated in various established and patient derived GBM cells when compared to normal astrocytes. To establish the functional significance of PELP1 in GBM, PELP1 expression was silenced using PELP1 specific siRNA and shRNA. We observed that silencing of PELP1 has a dramatic effect on cell proliferation, cell migration and colony formation of U87, T98G and LN229 GBM cells. Mechanistic studies showed that PELP1 interacts with β-catenin and silencing of PELP1 resulted in decrease in β-catenin reporter gene activation. Accordingly, PELP1 knockdown dramatically reduced the expression of β-catenin target genes such as Axin2, cyclin D1, c-Myc and MMP-2. Further, we demonstrated that silencing of PELP1 inhibited the accumulation and nuclear translocation of β-catenin. Chromatin-immunoprecipitation assay showed that silencing of PELP1 compromised the recruitment of β-catenin to the target genes promoter. In xenograft based tumorigenecity assays we found that silencing PELP1 dramatically reduced the in vivo tumor growth of U87 GBM cells. Taken together these results provide the first evidence that PELP1 could be a potential therapeutic target for therapeutic intervention in GBM. Citation Format: Gangadhara R. Sareddy, Pratibha Nutalapati, Rajeshwar R. Tekmal, Ratna K. Vadlamudi. The proto-oncogene Proline Glutamic acid Leucine rich Protein1 (PELP1) is a novel mediator of glioblastoma development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5190. doi:10.1158/1538-7445.AM2013-5190 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.