Expression of endoplasmic reticulum molecular chaperone Grp78 in human lung cancer and its clinical significance

Uramoto, Hidetaka; Sugio, Kenji; Oyama, Tsunehiro; Nakata, Shoji; Ono, Kenji; Yoshimastu, Takashi; Morita, Masaru; Yasumoto, Kosei

doi:10.1016/j.lungcan.2004.12.011

Cited by 141 publications

(104 citation statements)

References 41 publications

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“…Activation of the UPR has been reported in a wide variety of cancers, and there is extensive evidence for its in vivo activation in human tumours, (Fernandez et al, 2000;Shuda et al, 2003;Uramoto et al, 2005;Zhang et al, 2006;Scriven et al, 2007b;Al-Rawashdeh et al, 2008;Scriven et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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Activation and clinical significance of the unfolded protein response in breast cancer

et al. 2009

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Introduction: The tumour microenvironment is hypoglycaemic, hypoxic and acidotic. This activates a stress signalling pathway: the unfolded protein response (UPR). The UPR is cytoprotective if the stressor is mild, but may initiate apoptosis if severe. Activation of the UPR in breast carcinoma is induced by microenvironmental stress such as glucose and oxygen deprivation, but may also be linked to oestrogen stimulation. It may be clinically significant as it may alter chemosensitivity to doxorubicin. Methods: 395 human breast adenocarcinomas were immunohistochemically stained for UPR activation markers (glucose-regulated protein (GRP-78 and XBP-1). A model of UPR activation in vitro by glucose deprivation of T47D breast cancer cells was developed to determine how the UPR affects cellular sensitivity to doxorubicin and 5-fluorouracil. Cytotoxicity was assessed using a colorimetric cytotoxicity assay (MTT). The effect of oestrogen stimulation and tamoxifen exposure on UPR activation by T47D cells was determined by western blotting measurement of the key UPR protein, GRP-78. Results: Expression of GRP78 and XBP-1 was demonstrated in 76% and 90% of the breast cancers, respectively, and correlated with oestrogen receptor positivity ( P =0.045 and 0.017, respectively). In vitro UPR activation induced resistance to both doxorubicin and 5-flurouracil, ( P <0.05). Oestrogen stimulation induced GRP78 and XBP1 over-expression on western blotting. Tamoxifen did not block this response and may induce UPR activation in its own right. Conclusions: The UPR is activated in the majority of breast cancers and confers resistance to chemotherapy. In vitro oestrogen stimulates UPR induction. UPR activation may contribute to breast cancer chemoresistance and interact with oestrogen response elements.

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Section: Discussionmentioning

confidence: 99%

“…The UPR is activated in a range of human solid tumours including breast cancer (Fernandez et al, 2000), gastric cancer (Zhang et al, 2006;Scriven et al, 2007b), hepatocellular carcinoma (Shuda et al, 2003;Al-Rawashdeh et al, 2008), pancreatic cancer and lung cancer (Uramoto et al, 2005).…”

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confidence: 99%

Activation and clinical significance of the unfolded protein response in breast cancer

et al. 2009

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“…They express high levels of HSPs to prevent cellular and molecular damage and to prolong survival. 32,35,36 High levels of cell-surface-located GRP78 are found in and on a variety of carcinoma cells, such as breast cancer, [15][16][17] lung cancer, 40,41 gastric, 11,42 hepatocellular 43,44 and prostate cancers. 18,45 Histological examination of human prostate cancers demonstrated that GRP78 is clearly upregulated both intracellular and on the cell surface of aggressive tumors.…”

Section: Discussionmentioning

confidence: 99%

“…18,45 Histological examination of human prostate cancers demonstrated that GRP78 is clearly upregulated both intracellular and on the cell surface of aggressive tumors. 5,41 Overexpression of this chaperone obviously implicates higher drug resistance and a greater degree of malignancy, and is often associated with bad prognosis as reported in cases of breast, 14,17 prostate 5 and gastric cancer. 11 Zhang et al showed that levels of GRP78 expression in gastric primary tumors or metastatic lymph nodes correlate inversely with patient survival.…”

Section: Discussionmentioning

confidence: 99%

A new tumor-specific variant of GRP78 as target for antibody-based therapy

Rauschert

Brändlein

Holzinger

et al. 2008

Laboratory Investigation

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The chaperone GRP78 is a member of the heat-shock protein 70 (HSP70) family and is responsible for cellular homeostasis by preventing stress-induced apoptosis. GRP78 is expressed in all cells of the body. In malignant cells, which are permanently exposed to environmental stress, GRP78 is overexpressed and increased levels can be found in the cytoplasm and on the cell membrane. Thus, GRP78 promotes tumor proliferation, survival, metastases and resistance to a wide variety of therapies. Like other tumor-specific membrane molecules, GRP78 can also be present on cancer cells in a variant form. This modification qualifies it as a target for immune surveillance and antibody responses. The fully human monoclonal IgM antibody, SAM-6, was isolated from a gastric cancer patient and it binds to a new variant of GRP78 with a molecular weight of 82 kDa. The epitope is an O-linked carbohydrate moiety and is specific for malignant cells. These data show that cancer-specific modifications of cell-surface protection molecules are (a) subject of an immune response and (b) ideal targets for new therapeutical approaches.

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“…It is also reported that the redox imbalance due to hypoxic condition in cancer cells results in the activation of UPR pathway. Studies have also shown that Grp78 is highly expressed in prostate, lung, breast and colon cancers [74][75][76][77][78][79][80][81]. Furthermore, a study showed that cells which do not expresse Grp78 are unable to form tumor [82].…”

Section: Er Stress and Cancermentioning

confidence: 99%

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

2015

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Endoplasmic reticulum (ER) is the site of protein synthesis, protein folding, maintainance of calcium homeostasis, synthesis of lipids and sterols. Genetic or environmental insults can alter its function generating ER stress. ER senses stress mainly by three stress sensor pathways, namely protein kinase R-like endoplasmic reticulum kinase-eukaryotic translation-initiation factor 2a, inositol-requiring enzyme 1a-X-box-binding protein 1 and activating transcription factor 6-CREBH, which induce unfolded protein responses (UPR) after the recognition of stress. Recent studies have demonstrated that ER stress and UPR signaling are involved in cancer, metabolic disorders, inflammatory diseases, osteoporosis and neurodegenerative diseases. However, the precise knowledge regarding involvement of ER stress in different disease processes is still debatable. Here we discuss the possible role of ER stress in various disorders on the basis of existing literature. An attempt has also been made to highlight the present knowledge of this field which may help to elucidate and conjure basic mechanisms and novel insights into disease processes which could assist in devising better future diagnostic and therapeutic strategies.

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Expression of endoplasmic reticulum molecular chaperone Grp78 in human lung cancer and its clinical significance

Cited by 141 publications

References 41 publications

Activation and clinical significance of the unfolded protein response in breast cancer

Activation and clinical significance of the unfolded protein response in breast cancer

A new tumor-specific variant of GRP78 as target for antibody-based therapy

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

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