GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib

Kern, Johann; Untergasser, Gerold; Zenzmaier, Christoph; Sarg, Bettina; Gastl, Guenther; Gunsilius, Eberhard; Steurer, Michael

doi:10.1182/blood-2009-03-209668

Cited by 115 publications

(100 citation statements)

References 26 publications

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“…A possible explanation is that, as AKT and ERK can be stimulated by multiple pathways, in these ex vivo settings, ERK stimulation by TGFα is highly dependent on GRP78 levels in the isolated acinar clusters, whereas other mechanisms could compensate for GRP78 haploinsufficiency to activate AKT. This is in agreement with a published report that GRP78 induced a strong activation of ERK in endothelial cells and a weak activation of AKT (52). In these ex vivo cultures, TGFα did not stimulate p-STAT3 activation, and the ratio of p-STAT3 to total STAT3 level remained unchanged between c78 f/+ and control cells.…”

Section: Discussionsupporting

confidence: 81%

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

Shen

Zhu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini and PDAC of Pdx1-Cre;Kras G12D/+ ;p53 f/+ (PKC) mice as early as 2 mo, suggesting that GRP78 could exert a protective effect on acinar cells under stress, as during PDAC development. The PKC pancreata bearing wild-type Grp78 showed detectable PDAC by 3 mo and rapid subsequent tumor growth. In contrast, the PKC pancreata bearing a Grp78 f/+ allele (PKC78 f/+ mice) expressing about 50% of GRP78 maintained normal sizes during the early months, with reduced proliferation and suppression of AKT, S6, ERK, and STAT3 activation. Acinar-to-ductal metaplasia (ADM) has been identified as a key tumor initiation mechanism of PDAC. Compared with PKC, the PKC78 f/+ pancreata showed substantial reduction of ADM as well as pancreatic intraepithelial neoplasia-1 (PanIN-1), PanIN-2, and PanIN-3 and delayed onset of PDAC. ADM in response to transforming growth factor α was also suppressed in ex vivo cultures of acinar cell clusters isolated from mouse pancreas bearing targeted heterozygous knockout of Grp78 (c78 f/+ ) and subjected to 3D culture in collagen. We further discovered that GRP78 haploinsufficiency in both the PKC78 f/+ and c78 f/+ pancreata leads to reduction of epidermal growth factor receptor, which is critical for ADM initiation. Collectively, our studies establish a role for GRP78 in ADM and PDAC development.glucose-regulated protein 78 | GRP78 | pancreatic ductal adenocarcinoma | acinar-to-ductal metaplasia | Kras P ancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest diseases with limited therapeutic options and an overall 5-y survival rate of <10%; therefore, identification of targetable key players in tumor initiation as well as tumor maintenance is urgently needed (1). PDAC is believed to arise from a range of preneoplastic mucinous lesions with ductal morphology, pancreatic intraepithelial neoplasia (PanIN) being the most common in humans (2). About 90% of PDAC contains activating mutations of KRAS whereas 50-75% contain mutations in Tp53 (1). Mutationally activated oncogenic KRAS signals through the PI3K-PDK1-AKT pathway and the canonical mitogen-activated protein kinase pathway via RAF-MEK1/2-ERK1/2, as well as via positive feedback activation of receptor tyrosine kinases engaged by autocrine and paracrine stimuli (3). Although the histological appearance of PDAC suggests a ductal cell of origin, accumulating evidence reveals that PDAC originates primarily through transdifferentiation of acinar cells into ductal cells in a process referred to as acinar-to-ductal metaplasia (ADM), although centroacinar cells and pancreas precursor cells could also give rise to PDAC (2, 4, 5). To study PDAC, a pancreatic cancer mouse model mimicking human PDAC has been established using the pancreatic...

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Section: Discussionsupporting

confidence: 81%

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

Shen

Zhu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies using transmembrane prediction programs have suggested that GRP78 has four potential transmembrane domains at the cell surface: I (amino acids (aa) [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17], II (aa 29 -45), III (aa 222-242), and IV (aa 414 -431) (34). However, the studies performed here demonstrate that at least residues 416 -417 are exposed on the cell surface, as this is the sole SubA cleavage site, and we observe cell-surface cleavage.…”

Section: Discussionmentioning

confidence: 99%

“…Normal cellular function is, therefore, reestablished by reducing intermediate protein aggregates, increasing protein folding, regulating Ca 2ϩ , and repressing translation (1). In addition to its role as a molecular chaperone in the ER, GRP78 is found in the cytoplasm, nucleus, and mitochondria, and it exists in secreted and plasma membrane-associated forms (2)(3)(4)(5)(6). At the plasma membrane, GRP78 acts as a signaling receptor for activated ␣ 2 -macroglobulin (␣ 2 M*) (7,8).…”

mentioning

confidence: 99%

The Escherichia coli Subtilase Cytotoxin A Subunit Specifically Cleaves Cell-surface GRP78 Protein and Abolishes COOH-terminal-dependent Signaling

Ray

Ridder

et al. 2012

Journal of Biological Chemistry

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Background: GRP78 is aberrantly expressed on the surface of many different tumor cells where it functions as a growth factor-like receptor. Results: SubA cleavage of cell-surface GRP78 abrogates signaling initiated by ligation of the GRP78 COOH-terminal. Conclusion: SubA specifically cleaves cell-surface GPR78. Significance: SubA is a powerful tool that can be used to specifically probe the functions of cell-surface GPR78.

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“…Recent evidence has shown that GRP78 can be secreted by a variety of bortezomib-resistant solid tumor cell lines, and blocks the antiangiogenic activity of bortezomib through activation of ERK1/2 but inhibition of p53 (Kern et al, 2009). Whether GRP78 can be secreted from CRC cells?…”

Section: Discussionmentioning

confidence: 99%

“…Some solid tumor cells are able to secrete high amounts of GRP78, which blocks the antiangiogenic activity of Rong Fu 1& , Peng Yang 1& , Hai-Li Wu 1 , Zong-Wei Li 1 , Zhuo-Yu Li 1,2 * bortezomib through activation of extracellular signalrelated kinase and inhibition of p53 in endothelial cells (Kern et al, 2009). However, other biological roles of secreted GRP78 in tumor microenvironment and its action mode have not been identified.…”

Section: Introductionmentioning

confidence: 99%

GRP78 Secreted by Colon Cancer Cells Facilitates Cell Proliferation via PI3K/Akt Signaling

Fu¹,

Yang²,

Wu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Glucose regulated protein 78 (GRP78) is usually recognized as a chaperone in the endoplasmic reticulum. However, increasing evidence indicates that GRP78 can be translocated to the cell surface, acting as a signaling receptor for a variety of ligands. Since little is known about the secretion of GRP78 and its role in the progression of colon cancer we here focused on GRP78 from colon cancer cells, and purified GRP78 protein mimicking the secreted GRP78 was able to utilize cell surface GRP78 as its receptor, activating downstream PI3K/Akt and Wnt/β-catenin signaling and promote colon cancer cell proliferation. Our study revealed a new mode of action of autocrine GRP78 in cancer progression: secreted GRP78 binds to cell surface GRP78 as its receptor and activates intracellular proliferation signaling.

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GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib

Cited by 115 publications

References 26 publications

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

The Escherichia coli Subtilase Cytotoxin A Subunit Specifically Cleaves Cell-surface GRP78 Protein and Abolishes COOH-terminal-dependent Signaling

GRP78 Secreted by Colon Cancer Cells Facilitates Cell Proliferation via PI3K/Akt Signaling

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