αB-Crystallin Is Elevated in Highly Infiltrative Apoptosis-Resistant Glioblastoma Cells

Abstract

We have previously established two distinct glioma phenotypes by serial xenotransplantation of human glioblastoma (GBM) biopsies in nude rats. These tumors undergo a gradual transition from a highly invasive nonangiogenic to a less-invasive angiogenic phenotype. In a protein screen to identify molecular markers associated with the infiltrative phenotype, we identified ␣-basic-crystallin (␣Bc) , a small heatshock protein with cytoprotective properties. Its increased expression in the infiltrative phenotype was validated by immunohistochemistry and Western blots , confirming its identity to be tumor-derived and not from the host. Stereotactic human GBM biopsies taken from MRI-defined areas verified stronger ␣Bc expression in the infiltrative edge compared to the tumor core. Cell migration assays and immunofluorescence staining showed ␣Bc to be expressed by migrating cells in vitro. To determine ␣Bc function, we altered its expression levels. ␣Bc siRNA depletion caused a loss of migrating tumor cells from biopsy spheroids and delayed monolayer wound closure. In contrast, glioma cell migration in a Boyden chamber assay was unaffected by either ␣Bc knockdown or overexpression, indicating that ␣Bc is not functionally linked to the cell migration machinery. However, after siRNA ␣Bc depletion, a significant sensitization of cells to various apoptotic inducers was observed (actinomycin, tumor necrosis factor ␣, and TNF-related apoptosisinducing ligand [TRAIL]). In conclusion, ␣Bc is overexpressed by highly migratory glioma cells where it plays a functional role in apoptosis resistance. (Am J Pathol

Role of Small Heat Shock Protein HspB5 in Cancer

“…Elevated levels of HspB5 were demonstrated to occur in the more aggressive stages of gliomas. Especially the more infi ltrative glioblastoma cells showed higher levels of HspB5 (Goplen et al 2010 ). In breast cancer patients HspB5 expression was closely associated with advanced tumor grade progression, lymph vesicular invasion, and mortality, a phenomenon that was particularly observed in triple-negative breast tumors (Chelouche-Lev et al 2004 ;Kim et al 2011 ;Moyano et al 2006 ).…”

Chaperones: needed for both the good times and the bad times

“…sHSPs are holdases with documented roles in all major cellular processes. These include proteostasis [97][98][99][100][101], cell cycle control [102][103][104][105][106][107][108] and consequently metastasis [109][110][111][112][113][114]. CRYAB also inhibits apoptosis by binding to key regulators [115][116][117][118][119] and binds directly to mitochondria via VDAC and TOM20 in a stress-dependent manner [119,120].…”

The Dynamic Duo of Small Heat Proteins and IFs Maintain Cell Homeostasis, Resist Cellular Stress and Enable Evolution in Cells and Tissues

“…CRYAB expression in breast cancer is regulated by both TP53 and Ets1 (Bosman et al 2010 ). αB-crystallin is associated signifi cantly with ovarian (Volkmann et al 2012 ), glioblastoma (Goplen et al 2010 ) and hepatocellular carcinomas (Tang et al 2009 ). αB-crystallin in combination with HSPB2 promote tumour vascularization (Dimberg et al 2008 ) via a VEGF-A based mechanism (Kase et al 2010 ).…”

“…It binds directly to TP53 (Watanabe et al 2009 ;Liu et al 2007 ). In the canonical wnt-signalling pathway, αB-crystallin binds to the E-cadherin-β-catenin complex to maintain a membrane location for the complex ) Recent data suggest that αB-crystallin could regulate systemic expansion of IMCs through a cell-intrinsic mechanism (Dieterich et al 2013 ) Metastasis The direct involvement of αB-crystallin in the regulation of the cell cycle combined with the fact that the overexpression of αB-crystallin itself can complete the transformation process in immortalized human mammary epithelial cells (Moyano et al 2006 ) CRYAB is a marker of poor prognosis in cancer (Moyano et al 2006 ;Ivanov et al 2008 ) and its ability to prevent apoptosis contributes to the aggressiveness of these and other tumours (Goplen et al 2010 ;Volkmann et al 2012 ). CRYAB expression in breast cancer is regulated by both TP53 and Ets1 (Bosman et al 2010 ).…”