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Glucose-regulated protein 58 modulates ?-catenin protein stability in a cervical adenocarcinoma cell line.

ABSTRACT: BACKGROUND: Cervical cancer continues to threaten women's health worldwide, and the incidence of cervical adenocarcinoma (AD) is rising in the developed countries. Previously, we showed that glucose-regulated protein 58 (Grp58) served as an independent factor predictive of poor prognosis of patients with cervical AD. However, the molecular mechanism underlying the involvement of Grp58 in cervical carcinogenesis is currently unknown. METHODS: DNA microarray and enrichment analysis were used to identify the pathways disrupted by knockdown of Grp58 expression. RESULTS: Among the pathway identified, the WNT signaling pathway was one of those that were significantly associated with knockdown of Grp58 expression in HeLa cells. Our experiments showed that ?-catenin, a critical effector of WNT signaling, was stabilized thereby accumulated in stable Grp58 knockdown cells. Membrane localization of ?-catenin was observed in Grp58 knockdown, but not control cells. Using a transwell assay, we found that accumulated ?-catenin induced by Grp58 knockdown or lithium chloride treatment inhibited the migration ability of HeLa cells. Furthermore, an inverse expression pattern of Grp58 and ?-catenin was observed in cervical tissues. CONCLUSIONS: Our results demonstrate that ?-catenin stability is negatively regulated by Grp58 in HeLa cells. Overexpression of Grp58 may be responsible for the loss of or decrease in membranous ?-catenin expression in cervical AD.

SUBMITTER: Liao CJ

PROVIDER: S-EPMC4129111 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Glucose-regulated protein 58 modulates β-catenin protein stability in a cervical adenocarcinoma cell line.

Liao Chia-Jung CJ Wu Tzu-I TI Huang Ya-Hui YH Chang Ting-Chang TC Lai Chyong-Huey CH Jung Shih-Ming SM Hsueh Chuen C Lin Kwang-Huei KH

BMC cancer 20140801

<h4>Background</h4>Cervical cancer continues to threaten women's health worldwide, and the incidence of cervical adenocarcinoma (AD) is rising in the developed countries. Previously, we showed that glucose-regulated protein 58 (Grp58) served as an independent factor predictive of poor prognosis of patients with cervical AD. However, the molecular mechanism underlying the involvement of Grp58 in cervical carcinogenesis is currently unknown.<h4>Methods</h4>DNA microarray and enrichment analysis we ...[more]

PMID: 25081282

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Project description:BackgroundGlucose-regulated proteins (GRP) are induced in the cancer microenvironment to promote tumor survival, metastasis and drug resistance. AST was obtained from the medicinal plant Astragalus membranaceus, which possesses anti-tumor and pro-apoptotic properties in colon cancer cells and tumor xenograft. The present study aimed to investigate the involvement of GRP in endoplasmic reticulum (ER) stress-mediated apoptosis during colon cancer development, with focus on the correlation between AST-evoked regulation of GRP and calpain activation.MethodsThe effects of AST on GRP and apoptotic activity were assessed in HCT 116 human colon adenocarcinoma cells. Calpain activity was examined by using a fluorescence assay kit. Immunofluorescence staining and immunoprecipitation were employed to determine the localization and association between calpains and GRP. GRP78 gene silencing was performed to confirm the importance of GRP in anticancer drug activities. The modulation of GRP and calpains was also studied in nude mice xenograft.ResultsER stress-mediated apoptosis was induced by AST, as shown by elevation in both spliced XBP-1 and CHOP levels, with parallel up-regulation of GRP. The expression of XBP-1 and CHOP continued to increase after the peak level of GRP was attained at 24 h. Nevertheless, the initial increase in calpain activity as well as calpain I and II protein level was gradually declined at later stage of drug treatment. Besides, the induction of GRP was partly reversed by calpain inhibitors, with concurrent promotion of AST-mediated apoptosis. The knockdown of GRP78 by gene silencing resulted in higher sensitivity of colon cancer cells to AST-induced apoptosis and reduction of colony formation. The association between calpains and GRP78 had been confirmed by immunofluorescence staining and immunoprecipitation. Modulation of GRP and calpains by AST was similarly demonstrated in nude mice xenograft, leading to significant inhibition of tumor growth.ConclusionsOur findings exemplify that calpains, in particular calpain II, play a permissive role in the modulation of GRP78 and consequent regulation of ER stress-induced apoptosis. Combination of calpain inhibitors and AST could exhibit a more pronounced pro-apoptotic effect. These results help to envisage a new therapeutic approach in colon cancer by targeting calpain and GRP.

Dataset Information

Glucose-regulated protein 58 modulates ?-catenin protein stability in a cervical adenocarcinoma cell line.

Publications

Glucose-regulated protein 58 modulates β-catenin protein stability in a cervical adenocarcinoma cell line.

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