Increased expression of GRP94 protein is associated with decreased sensitivity to X-rays in cervical cancer cell lines

Kubota, Hisayo; Suzuki, Toshikazu; Lu, Jun; Takahashi, Shunji; Sugita, Katsuo; Sekiya, Souei; Suzuki, Nobuo

doi:10.1080/09553000500434727

Cited by 49 publications

(30 citation statements)

References 34 publications

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“…Paradoxically, GRP94 overexpression has been previously linked with cellular transformation, tumorigenicity and decreased radiosensitivity, as well as increased resistance to pro-apoptotic etoposide chemotherapy [40][41][42]. Therefore, at least superficially, the observed suppression in metastatic cells in the current study seems contradictory to previous findings.…”

Section: Discussioncontrasting

confidence: 82%

Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer

Howard

Leung

Yuen

et al. 2008

Clin Exp Metastasis

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The presence of circulating tumor cells (CTC) is common in prostate cancer patients, however until recently their clinical significance was unknown. The CTC stage is essential for the formation of distant metastases, and their continuing presence after radical prostatectomy has been shown to predict recurrent or latent disease. Despite their mechanistic and prognostic importance, due both to their scarcity and difficulties in their isolation, little is known about the characteristics that enable their production and survival. The aim of this study was to investigate the molecular mechanisms underlying the survival of CTC cells. A novel CTC cell line from the bloodstream of an orthotopic mouse model of castration-resistant prostate cancer was established and compared with the primary tumor using attachment assays, detachment culture, Western blot, flow cytometry and 2D gel electrophoresis. Decreased adhesiveness and expression of adhesion molecules E-cadherin, beta4-integrin and gamma-catenin, together with resistance to detachment and drug-induced apoptosis and upregulation of Bcl-2 were integral to the development of CTC and their survival. Using proteomic studies, we observed that the GRP94 glycoprotein was suppressed in CTC. GRP94 was also shown to be suppressed in a tissue microarray study of 79 prostate cancer patients, indicating its possible role in prostate cancer progression. Overall, this study suggests molecular alterations accounting for the release and survival of CTC, which may be used as drug targets for either anti-metastatic therapy or the suppression of latent disease. We also indicate the novel involvement of GRP94 suppression in prostate cancer metastasis.

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Section: Discussioncontrasting

confidence: 82%

Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer

Howard

Leung

Yuen

et al. 2008

Clin Exp Metastasis

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“…In addition, targeting cancer cells with an antisense or RNAi procedure against Grp94 has shown increased chemosensitivity or radiosensitivity (Reddy et al, 1999;Kubota et al, 2005). From the therapeutic standpoint, this evidence may provide a novel/effective approach for treating human OSCCs.…”

Section: Discussionmentioning

confidence: 99%

Network-based analysis of calcium-binding protein genes identifies Grp94 as a target in human oral carcinogenesis

et al. 2007

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To characterise Ca 2 þ -binding protein gene expression changes in oral squamous cell carcinomas (OSCCs), we compared the gene expression profiles in OSCC-derived cell lines with normal oral tissues. One hundred Ca 2 þ -binding protein genes differentially expressed in OSCCs were identified, and genetic pathways associated with expression changes were generated. Among genes mapped to the network with the highest significance, glucose-regulated protein 94 kDa (Grp94) was evaluated further for mRNA and protein expression in the OSCC cell lines, primary OSCCs, and oral premalignant lesions (OPLs). A significant (Po0.001) overexpression of Grp94 protein was observed in all cell lines compared to normal oral epithelium. Immunohistochemical analysis showed highly expressed Grp94 in primary OSCCs and OPLs, whereas most of the corresponding normal tissues had no protein immunoreaction. Real-time quantitative reverse transcriptase-PCR data agreed with the protein expression status. Moreover, overexpression of Grp94 in primary tumours was significantly (Po0.001) correlated with poor disease-free survival. The results suggested that Grp94 may have potential clinical application as a novel diagnosis and prognostic biomarker for human OSCCs.

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“…In cervical cancer cell lines, the UPR-related proteins such as Grp78, Grp94 and activating transcription factor 4 (ATF4) are associated with tolerance to ER stress, apoptosis and sensitivities to X-ray and anticancer drugs. (34)(35)(36)(37) However, the expression and prognostic value of UPR-related protein in cervical cancer are largely unknown. Grp58 is also a type of ER stress-responsive protein.…”

Section: Discussionmentioning

confidence: 99%

Glucose‐regulated protein 58 modulates cell invasiveness and serves as a prognostic marker for cervical cancer

Liao

Huang

et al. 2011

Cancer Science

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Human papilloma virus infection is critical but not sufficient to cause cervical cancer. Molecular markers of cervical carcinogenesis are essential. The aim of this study was to identify aberrantly expressed proteins in cervical cancer and determine their clinical significance. A two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomic strategy was used for screening candidate proteins. Immunoblotting and immunohistochemical (IHC) analyses were performed to confirm the results of 2-DE, and the clinical significance was estimated. Glucose-regulated protein 58 (Grp58) was overexpressed in 73% of cancers. The IHC staining showed that the Grp58 histoscore was significantly higher in patients with adenocarcinoma (AD) compared with squamous cell carcinoma (P < 0.05). Grp58 staining was intense in AD with a penetration depth greater than half of the cervical stroma (P = 0.033). High Grp58 expression was associated with low overall survival and recurrence-free survival (RFS) rates (P = 0.007 and P = 0.013, respectively). In multivariate analysis, high Grp58 expression (P = 0.042) and lymph node metastasis (P = 0.026) were determined as independent prognostic factors for RFS. Patients exhibiting both high Grp58 expression and lymph node metastasis displayed poorer outcomes than the other patient groups. In functional studies, knockdown of Grp58 in HeLa cells led to decreased cell invasiveness and inhibition of lung metastasis in a xenograft mouse model. In conclusion, Grp58 serves as a potent prognostic factor of cervical AD. Estimation of the Grp58 index in conjunction with the lymph node metastasis status might aid in predicting the prognosis of cervical AD. (Cancer Sci 2011; 102: 2255-2263 C ervical cancer is one of the most common cancers among women worldwide. Approximately 500 000 diagnoses of cervical cancer are made each year, leading to 274 000 deaths, although the incidence and death rate have declined markedly in the past three decades because of effective screening.(1) Human papillomaviruses (HPV) are the causative agents of over 99% of cervical cancers containing viral sequences. Infection by highrisk HPV types is necessary but not sufficient for progression to cancer. Most HPV infections are transient without clinical manifestation and are cleared naturally; <1% of women become HPV carriers and remain at high risk of developing cervical cancer.(2)The mechanisms underlying the progression and regression of lesions caused by HPV infection are unknown, and further investigation of the molecular alterations in cervical cancer is needed.Glucose-regulated protein 58 (Grp58) is a glycoprotein-specific thiol-oxidoreductase belonging to the disulfide isomerase family of proteins. Grp58 is a multifunctional protein.(3) Recent studies suggest that Grp58 plays a role in cancer, although related information is limited. Hirano et al.(4) demonstrated that enhanced expression of Grp58 was associated with oncogenic transformation in normal rat kidney cells. Grp58 overexpression modulates STAT3 signaling in cancer...

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Increased expression of GRP94 protein is associated with decreased sensitivity to X-rays in cervical cancer cell lines

Cited by 49 publications

References 34 publications

Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer

Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer

Network-based analysis of calcium-binding protein genes identifies Grp94 as a target in human oral carcinogenesis

Glucose‐regulated protein 58 modulates cell invasiveness and serves as a prognostic marker for cervical cancer

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