Cell Surface-bound Heat Shock Protein 70 (Hsp70) Mediates Perforin-independent Apoptosis by Specific Binding and Uptake of Granzyme B

Groß, Catharina C.; Koelch, Walter; DeMaio, Antonio; Arispe, Nelson; Multhoff, Gabriele

doi:10.1074/jbc.m302644200

Cited by 173 publications

(148 citation statements)

References 45 publications

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“…Antibodies to the Hsp70 peptide TKD have the capacity to block chemoattraction of NK cells and prevent granzyme Bmediated killing of tumor cells. 13,26,27 Our findings that Hsp70 surface expression by tumor cells is associated with a positive prognosis in colon and gastric cancers are consistent with data that show NK cells selectively target and lyse Hsp70 membrane-positive tumor cells. However, this interpretation is apparently contradicted by findings that Hsp70 surface expression is not associated with a positive outcome in lower rectal or squamous cell carcinomas of the lung.…”

Section: Discussionsupporting

confidence: 78%

Patient survival by Hsp70 membrane phenotype

Pfister

Radons

Busch

et al. 2007

Cancer

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BACKGROUNDHeat shock proteins (HSPs) play important roles in tumor immunity. The authors prospectively investigated the correlation between the tumor‐specific Hsp70 membrane expression as an independent clinicopathological marker and overall survival in tumor entities that differ in their route of metastasis.METHODSHsp70 membrane expression was examined by flow cytometry in 58 colon, 19 gastric, 54 lower rectal carcinoma, and 19 squamous cell carcinoma specimens and the corresponding normal tissues at time of first diagnosis. Kaplan‐Meier survival curves were analyzed to determine the relation of Hsp70 expression to the patients' prognosis.RESULTSAn Hsp70 membrane‐positive phenotype was found in 40% (colon), 37% (gastric), 43% (lower rectal), and 42% (squamous cell) of the analyzed tumor specimens. None of the corresponding normal tissues was found to be Hsp70 membrane‐positive. In patients with colon (P = .032) and gastric (P = .045) carcinomas, an Hsp70 membrane expression correlated significantly with an improved overall survival; a negative association was seen in lower rectal (P = .085) and squamous cell carcinoma (P = .048).CONCLUSIONSThe authors hypothesized that differing relations between surface expression of Hsp70 on tumor cells and clinical outcomes may reflect differences in the route of metastases. Colon and gastric carcinomas metastasize into the liver where hepatic natural killer cells may have the capacity to recognize and kill Hsp70 membrane‐positive tumor cells and thus account for a better overall survival. Cancer 2007; 110:926–35. © 2007 American Cancer Society.

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Section: Discussionsupporting

confidence: 78%

Patient survival by Hsp70 membrane phenotype

Pfister

Radons

Busch

et al. 2007

Cancer

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“…The mechanism of lysis after contact of NK cells with Hsp70 was identified as granzyme B-mediated apoptosis. 44 These data indicated that only Hsp70 or a peptide derived thereof, but not Bag-4 and Hsp40, provided the target structure for NK cell-mediated Recently, several cell surface molecules, including CD40 on B cells, 45 CD14 and toll-like receptors on monocytes and dendritic cells, 46 and CD91 on macrophages, 47 were discussed as potential receptors for HSPs on immunoregulatory cells. The interaction of NK cells with Hsp70 and Hsp70 peptide was found to be mediated through the C-type lectin receptor CD94.…”

Section: Discussionmentioning

confidence: 99%

Dual function of membrane-bound heat shock protein 70 (Hsp70), Bag-4, and Hsp40: protection against radiation-induced effects and target structure for natural killer cells

et al. 2004

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CX þ /CXÀ and Colo þ /ColoÀ tumor sublines with stable heat shock protein 70 (Hsp70) high and low membrane expression were generated by fluorescence activated cell sorting of the parental human colon (CX2) and pancreas (Colo357) carcinoma cell lines, using an Hsp70-specific antibody. Two-parameter flow cytometry revealed that Hsp70 colocalizes with Bag-4, also termed silencer of death domain, not only in the cytosol but also on the plasma membrane. After nonlethal c-irradiation, the percentage of membranepositive cells and the protein density of Hsp70 and Bag-4 were found to be strongly upregulated in carcinoma sublines with initially low expression levels (CXÀ, ColoÀ). Membrane expression of Hsp70 was also elevated in Bag-4 overexpressing HeLa cervix carcinoma cells when compared to neo-transfected cells. In response to c-irradiation, neotransfected HeLa cells behaved like Hsp70/Bag-4 lowexpressing CXÀ and ColoÀ, and Bag-4-transfected HeLa cells like Hsp70/Bag-4 high-expressing carcinoma sublines CX þ and Colo þ . Immunoprecipitation studies further confirmed colocalization of Hsp70 and Bag-4 but also point to an association of Hsp70 and Hsp40 on the plasma membrane of CX þ and Colo þ cells; on CXÀ and ColoÀ tumor sublines, Hsp40 was detectable in the absence of Hsp70 and Bag-4. Other co-chaperones including Hsp60 and Hsp90 were neither found on the cell surface of CX þ /CXÀ, Colo þ /ColoÀ nor on HeLa neo-/HeLa Bag-4-transfected tumor cells. Functionally, Hsp70/Bag-4 and Hsp70/Hsp40 membrane-positive tumor cells appeared to be better protected against radiation-induced effects, including G2/M arrest and growth inhibition, on the one hand. On the other hand, membrane-bound Hsp70, but neither Bag-4 nor Hsp40, served as a recognition site for the cytolytic attack mediated by natural killer cells.

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“…For example, bacterial and viral endosomolysins can substitute for perforin in vitro [and are widely used as laboratory reagents for intracellular delivery (84)] and may potentially play a similar role in vivo. The heat shock protein hsp70, which is known to chaperone some peptides across cell membranes, can also carry GzmB (and presumably other granyzmes) into cells (85). Hsp70 is found on the surface of some stressed cells or tumor cells and may help to remove these cells from the body.…”

Section: Granzyme Release Uptake and Trafficking In Target Cellsmentioning

confidence: 99%

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Chowdhury

Lieberman

2008

Annu. Rev. Immunol.

569

580

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The granzymes are cell death-inducing enzymes, stored in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, that are released during granule exocytosis when a specific virus-infected or transformed target cell is marked for elimination. Recent work suggests that this homologous family of serine esterases can activate at least three distinct pathways of cell death. This redundancy likely evolved to provide protection against pathogens and tumors with diverse strategies for evading cell death. This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.

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Cell Surface-bound Heat Shock Protein 70 (Hsp70) Mediates Perforin-independent Apoptosis by Specific Binding and Uptake of Granzyme B

Cited by 173 publications

References 45 publications

Patient survival by Hsp70 membrane phenotype

Patient survival by Hsp70 membrane phenotype

Dual function of membrane-bound heat shock protein 70 (Hsp70), Bag-4, and Hsp40: protection against radiation-induced effects and target structure for natural killer cells

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

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