Cell cycle progression via activation of cyclin dependent kinases (Cdks) is one of the hallmarks of cancer. The action G1 Cdks, Cdk4 and Cdk6, represent an essential step from quiescent to transformed phenotype. Factors that inhibit Cdk4/6 activation have tumor suppressor qualities, and these are often inhibited in human cancers. By contrast, Cdk4/6 activators, such as cyclin D are upregulated and are associated with poor prognosis. The balance between Cdk inhibitors (such as p16INK4 family) and activators (cyclin D), while important, do not represent the sole regulators of kinase activity. The interest in molecular chaperones and their roles in cellular quality control is centered on the therapeutic potential of Hsp90 inhibitors, such as 17- AAG, that promote rapid degradation of several kinases including Cdk4. In addition, Cdc37 expression is strongly correlated with cell proliferation and is extremely low in quiescent cells and healthy adult tissues. In this pilot project, we will address the role of Cdc37 expression as an early biomarker of liver cell proliferation and in addition test the role of geldanamycin as a therapeutic agent toward HCC.
Specific aim 1. Characterize the role of Cdc37 as an early biomarker of HCC. We will measure Cdc37 protein levels in sections of human liver from biopsy samples. We will determine its distribution among different cell types in healthy liver and its levels in neoplastic nodules and advanced HCC. These studies will use standard histopathological staining procedures using antisera specific to Cdc37.
Specific aim 2. Determine the therapeutic potential of Hsp90 inhibitors toward HCC. We will first determine the sensitivity of primary human hepatocytes toward 17-AAG in comparison to HCC cell lines and immortalized liver cells. This will involve analysis of protein kinase stability and cell viability after drug treatment.
|Arriazu, Elena; Ge, Xiaodong; Leung, Tung-Ming et al. (2017) Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury. Gut 66:1123-1137|
|Renault, Thibaud T; Luna-Vargas, Mark P A; Chipuk, Jerry E (2016) Mouse Liver Mitochondria Isolation, Size Fractionation, and Real-time MOMP Measurement. Bio Protoc 6:|
|Kocabayoglu, Peri; Lade, Abigale; Lee, Youngmin A et al. (2015) ?-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J Hepatol 63:141-7|
|Renault, Thibaud T; Floros, Konstantinos V; Elkholi, Rana et al. (2015) Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis. Mol Cell 57:69-82|
|Hasegawa, Daisuke; Calvo, Veronica; Avivar-Valderas, Alvaro et al. (2015) Epithelial Xbp1 is required for cellular proliferation and differentiation during mammary gland development. Mol Cell Biol 35:1543-56|
|Lu, Yongke; Ward, Stephen C; Nieto, Natalia (2014) Ethanol plus the Jo2 Fas agonistic antibody-induced liver injury is attenuated in mice with partial ablation of argininosuccinate synthase. Alcohol Clin Exp Res 38:649-56|
|Lade, Abigale; Noon, Luke A; Friedman, Scott L (2014) Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis, hepatic fibrosis, and cancer. Curr Opin Oncol 26:100-7|
|Jiao, Jingjing; Dragomir, Ana-Cristina; Kocabayoglu, Peri et al. (2014) Central role of conventional dendritic cells in regulation of bone marrow release and survival of neutrophils. J Immunol 192:3374-82|
|Renault, Thibaud T; Elkholi, Rana; Bharti, Archana et al. (2014) B cell lymphoma-2 (BCL-2) homology domain 3 (BH3) mimetics demonstrate differential activities dependent upon the functional repertoire of pro- and anti-apoptotic BCL-2 family proteins. J Biol Chem 289:26481-91|
|Howarth, Deanna L; Lindtner, Claudia; Vacaru, Ana M et al. (2014) Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish. PLoS Genet 10:e1004335|
Showing the most recent 10 out of 84 publications