Overexpression of glucose-regulated protein 78 in colon cancer

Xing, Xiaoming; Lai, Maode; Wang, Yinghong; Xu, Enbo; Huang, Qiong

doi:10.1016/j.cca.2005.07.016

Cited by 115 publications

(82 citation statements)

References 18 publications

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“…14,15) Moreover, the expression of GRP78 has been shown to be elevated in a variety of tumors, including prostate, lung, breast, colon, and gastric tumors. [16][17][18][19] According to these observations, GRP78 is a potential target for cancer therapy.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of Cancer Cell Growth by GRP78 siRNA Lipoplex <i>via</i> Activation of Unfolded Protein Response

Matsumura

Sakai

Kawakami

et al. 2014

Biological & Pharmaceutical Bulletin

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Proteasome inhibitors are a novel class of molecular-targeted anti-cancer drugs that suppress the degradation of malfolded proteins, trigger endoplasmic reticulum (ER) stress, and activate apoptosis signals. Glucose-regulated protein 78 (GRP78), a major ER chaperone, is one of the most important molecules for transduction of unfolded protein response (UPR) signals. In accordance with past findings that expression of GRP78 is elevated in cancer cells and helps to resist stress-induced apoptosis, GRP78 knockdown could be effective in anticancer therapy. We tested this hypothesis and found that transfection of small interfering RNA (siRNA) targeting GRP78 inhibited the growth of RENCA renal carcinoma cells, in association with elevated gene expression of UPR downstream signaling molecules (CHOP, EDEM1, and ERdj4 mRNA). In addition, the combinatorial effect of GRP78 siRNA with ER stress inducers (tunicamycin, MG132, and 2-deoxyglucose) on survival was measured. Combination of GRP78 siRNA and the ER stress inducers more extensively reduced cell viability than combination with scrambled siRNA. Besides RENCA, B16BL6 melanoma cells were also shown to be sensitive to GRP78 siRNA. These results suggest that GRP78 knockdown might be an effective strategy for cancer therapy targeting UPR-induced apoptosis.Key words glucose-regulated protein 78; small interfering RNA; apoptosis; unfolded protein response; endoplasmic reticulum stress; cancer cellThe endoplasmic reticulum (ER) is responsible for protein synthesis, conformational maturation, and quality control of correctly folded proteins. In cancer cells, protein synthesis and by-product disposal are elevated, therefore, disruption of ER functions is believed to be a promising approach for cancer therapy. Proteasome inhibitors, which are a novel class of molecular-targeted anti-cancer drugs, suppress the degradation of malfolded proteins and trigger ER stress, which leads to the activation of the unfolded protein response (UPR) and subsequent apoptotic signals.1,2) Bortezomib was the first approved proteasome inhibitor, and is used for the treatment of relapsed multiple myeloma 3) and mantle cell lymphoma. 4) A second generation of proteasome inhibitors are now under development to improve drug efficacy and compliance. 5)Molecular chaperones are key factors involved in unfolded protein accumulation. Glucose-regulated protein 78 (GRP78) is known as a stress-inducible ER chaperone protein and serves as an ER stress signal regulator.6) Under unstressed conditions, GRP78 associates with ER transmembrane sensor proteins, such as protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1) and activating transcription factor 6 (ATF6), 7,8) and these interactions maintain them in an inactive form. However, accumulation of unfolded proteins results in the detachment of GRP78 from the sensor proteins and the subsequent activation of the unfolded protein response (UPR), which results in general translational attenuation, up-regulation of chaperones a...

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Section: Discussionmentioning

confidence: 98%

Inhibition of Cancer Cell Growth by GRP78 siRNA Lipoplex <i>via</i> Activation of Unfolded Protein Response

Matsumura

Sakai

Kawakami

et al. 2014

Biological & Pharmaceutical Bulletin

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“…Primary human tumor cells of several origins, including breast (25), lung (26), liver (27), colon (28), prostate (29), and brain (30), were shown to upregulate UPR pathways, including GRP78, ATF6, and XBP-1 splicing, whereas peritumoral areas do not. Additionally, in primary human melanoma, liver, and breast cancer specimens, the level of GRP78 positively correlates with tumor progression (25,27,31).…”

Section: The Upr Is Activated In Tumors and Is Essential For Tumorigementioning

confidence: 99%

Tumor Stress Inside Out: Cell-Extrinsic Effects of the Unfolded Protein Response in Tumor Cells Modulate the Immunological Landscape of the Tumor Microenvironment

Mahadevan

Zanetti

2011

The Journal of Immunology

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The unfolded protein response (UPR) is a eukaryotic cellular adaptive mechanism that functions to cope with stress of the endoplasmic reticulum (ER). Accumulating evidence demonstrates that the tumor microenvironment contains stressors that elicit a UPR, which has been demonstrated to be a cell-intrinsic mechanism crucial for tumorigenesis. In addition, the UPR is a source of proinflammatory signaling whose downstream mediators may hamper antitumor immunity. We discuss how the UPR may impair Ag presentation, which could result in defective T cell priming, also leading to tumor escape and growth. Further, we discuss the recent finding that ER stress and attendant proinflammation can be transmitted from ER-stressed tumor cells to myeloid cells. The ideas presented suggest that, in addition to being a cell-intrinsic mechanism of tumor survival, the tumor UPR can serve as a cell-extrinsic regulator of tumorigenesis by remodeling the immune response in the tumor microenvironment.

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“…Therefore, it appears to play cytoprotective and antiapoptotic functions. Recently, Grp78 expression was found elevated in many tumors and cancer cell lines, including lung (6, 7), breast (8,9), stomach (10,11), prostate (12,13), colon (14), and liver (15,16) cells. However, it is unclear whether and how of this molecule play roles associated with oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

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

Chiu

Lin

Lee³

et al. 2008

Molecular Cancer Therapeutics

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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]

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Overexpression of glucose-regulated protein 78 in colon cancer

Cited by 115 publications

References 18 publications

Inhibition of Cancer Cell Growth by GRP78 siRNA Lipoplex <i>via</i> Activation of Unfolded Protein Response

Inhibition of Cancer Cell Growth by GRP78 siRNA Lipoplex <i>via</i> Activation of Unfolded Protein Response

Tumor Stress Inside Out: Cell-Extrinsic Effects of the Unfolded Protein Response in Tumor Cells Modulate the Immunological Landscape of the Tumor Microenvironment

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

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