Glucose-regulated protein 78 regulates multiple malignant phenotypes in head and neck cancer and may serve as a molecular target of therapeutic intervention

Abstract

Glucose-regulated protein 78 (Grp78) is an endoplasmic reticulum chaperone protein and is overexpressed in various cancers. However, it is unclear how significance of this molecule play an active role contributing to the oncogenic effect of head and neck cancer (HNC). To investigate the potential function of Grp78, six HNC cell lines were used. We found that Grp78 is highly expressed in all six cell lines and many of the proteins were localized in the periphery regions, implying other function of this molecule aside from endoplasmic reticulum stress response. Knockdown of Grp78 by small interfering RNA significantly reduced cell growth and colony formation to 53% to 12% compared with that of controls in all six HNC cell lines. Using in vitro wound healing and Matrigel invasion assays, we found that cell migration and invasive ability were also inhibited to 23% to 2% in all these cell lines tested. In vivo xenograft studies showed that administration of Grp78-small interfering RNA plasmid into HNC xenografts significantly inhibited both tumor growth in situ (>60% inhibition at day 34) and liver metastasis (>90% inhibition at day 20). Our study showed that Grp78 actively regulates multiple malignant phenotypes, including cell growth, migration, and invasion. Because knockdown Grp78 expression succeeds in the reduction of tumor growth and metastatic potential, this molecule may serve as a molecular target of therapeutic intervention for HNC. [Mol Cancer Ther 2008; 7(9):2788 -97]

Molecular Chaperones as a Common Set of Proteins That Regulate the Invasion Phenotype of Head and Neck Cancer

“…11). All the cell culture conditions were the same as previously reports (9)(10)(11). The Matrigel invasion method was used to establish HNC cell sublines with a high invasive capability, similar to what has been previously described (12).…”

“…For cellular transfection, the Lipofectamine 2000 reagent and Opti-MEM medium (Invitrogen) were used, as previous described (10,11).…”

Downregulation of Ches1 and other novel genes in oral cancer cells chronically exposed to areca nut extract

“…The oral cancer cell lines OECM1 and SAS were used and maintained, as previously described. 11,12 For each cell line, the IC70 dose of areca nut extract was determined by calculating the concentration at which there was 70% cell viability after 24 hours of treatment. The areca nut extracttrained sublines were established by chronically treating cells with areca nut extract at IC70 doses for 30 passages.…”

“…The RNA extraction and microarray analyses were similar, as previously described. 11 Briefly, the Affymetrix U133A microarray and scanning systems were used. The functional network analyses of differentially expressed genes were performed using the MetaCore Analytical suite (GeneGo, St Joseph, MI).…”

Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells

“…Unresolved and protracted ER stress-triggered apoptosis involves the induction of BH3 domain-only proteins BIK and BIM (8,9), as well as the activation of the intrinsic pathway of apoptosis involving the activity of caspase-9, caspase-3, and caspase-7 (10,11). Intracellular proteotoxic stress and UPR is a common accompaniment of cancer cell transformation (12)(13)(14). Consistent with this, elevated levels of protective GRP78 have been shown to have an important role in the pathogenesis of several types of cancers, in which it confers poor prognosis (15,16).…”