Abstract 3845: Endocytic protein APPL2 as a regulator of glioblastoma cell growth
Authors: Pyrzynska Beata , Banach-Orlowska Magdalena , Teperek Marta , Miekus Katarzyna , Drabik Grazyna , Majka Marcin , Miaczynska Marta 
Published: June 2012

Recent discoveries have suggested that some endocytic proteins are involved in multiple steps of cellular signaling, which starts from endocytosis of activated receptors and is further transmitted from the cytoplasm to the nucleus. Two homologous adaptor proteins APPL1 and APPL2 seem to constitute good examples of such proteins, involved in both endocytosis (by interacting with small GTPase Rab5) and cellular signaling. They are able to translocate to the nucleus and may participate in the regulation of chromatin modification, raising a possibility of their involvement in the control of gene transcription.

Deregulation of such important cellular functions may be a cause of neoplastic growth and tumorigenesis. In fact, there are some lines of evidence suggesting a possible role for APPL proteins in cancer development and/or progression: 1) APPL proteins participate in endocytic trafficking of several transmembrane receptors and defective degradation (via deregulation of endocytosis) of the receptor tyrosine kinases, like EGFR, leads to sustained signaling, changes in cell proliferation or transformation; 2) APPL proteins can also increase activity the key kinase involved in the regulation of tumorigenesis – AKT, by interacting with several components of its signaling pathway, like PI3K, AKT itself, GSK3β and TSC2. Indeed both APPL proteins appear to be required for HGF-induced cell survival and migration via activation of AKT.

Many major genomic abnormalities in human glioblastoma (GBM) samples, recently cataloged by the TCGA Research Network, result in aberrations of signaling molecules and pathways potentially regulated by APPL proteins, like receptor tyrosine kinases and AKT, highlighting their importance for GBM development. Taking in consideration all the facts mentioned above, we have chosen GBM as a model to study the potential role of APPL proteins in the regulation of tumor growth.

During our study we have discovered the following phenomena:

i) The level of APPL2 protein (but not APPL1) is significantly increased in 40% of human GBM versus normal brain samples.

ii) Silencing of APPL2 in GBM cell lines decreases both anchorage-independent growth and cell viability under reduced growth factor availability. These effects result from both: inhibition of cell proliferation and increased apoptosis.

iii) Expression of some cell cycle- and apoptosis-related genes changes upon APPL2 silencing.

To our knowledge these results for the first time show the upregulation of APPL2 protein in human tumor samples suggesting that this protein may provide some advantage for tumor growth. The results of in vitro experiments explain the mechanism by demonstrating that APPL2 influences both cell proliferation and resistance to apoptosis. Our results also highlight the surprising differences in the functions of homologous APPL1 and APPL2 proteins that will be further discussed.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3845. doi:10.1158/1538-7445.AM2011-3845