Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

Tufi, Roberta; Panaretakis, Theocharis; Bianchi, Katiuscia; Criollo, Alfredo; Fazi, Barbara; Sano, Federica Di; Tesnière, Antoine; Kepp, Oliver; Paterlini‐Bréchot, Patrizia; Zitvogel, Laurence; Piacentini, Mauro; Szabadkai, György; Kroemer, Guido

doi:10.1038/sj.cdd.4402275

Cited by 108 publications

(91 citation statements)

References 42 publications

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“…SERCA usually mediates the ATP-driven uptake of cytosolic Ca 2 þ into the ER lumen, meaning that its inhibition by THAPS causes a relative depletion of luminal Ca 2 þ (Lytton et al, 1991). In this context it appears intriguing that previous investigations on human neuroblastoma cells that were defective in the anthracycline-elicited CRT exposure pathway, led to the conclusion that two manipulations designed to lower luminal ER Ca 2 þ , namely overexpression of reticulon 1C and targeted expression of the ligand-binding domain of the IP 3 receptor, both could bypass this defect and enhance CRT exposure (Tufi et al, 2008). The data reported here underscore the importance of ER Ca 2 þ fluxes for the translocation of CRT to the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress

et al. 2010

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In contrast to other cytotoxic agents including anthracyclins and oxaliplatin (OXP), cisplatin (CDDP) fails to induce immunogenic tumor cell death that would allow to stimulate an anticancer immune response and hence to amplify its therapeutic efficacy. This failure to induce immunogenic cell death can be attributed to CDDP's incapacity to elicit the translocation of calreticulin (CRT) from the lumen of the endoplasmic reticulum (ER) to the cell surface. Here, we show that, in contrast to OXP, CDDP is unable to activate the protein kinase-like ER kinase (PERK)-dependent phosphorylation of the eukaryotic translation initiation factor 2a (eIF2a). Accordingly, CDDP also failed to stimulate the formation of stress granules and macroautophagy, two processes that only occur after eIF2a phosphorylation. Using a screening method that monitors the voyage of CRT from the ER lumen to the cell surface, we identified thapsigargin (THAPS), an inhibitor of the sarco/ER Ca 2 þ -ATPase as a molecule that on its own does not stimulate CRT exposure, yet endows CDDP with the capacity to do so. The combination of ER stress inducers (such as THAPS or tunicamycin) and CDDP effectively induced the translocation of CRT to the plasma membrane, as well as immunogenic cell death, although ER stress or CDDP alone was insufficient to induce CRT exposure and immunogenic cell death. Altogether, our results underscore the contribution of the ER stress response to the immunogenicity of cell death.

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Section: Discussionmentioning

confidence: 99%

Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress

et al. 2010

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“…54 Trypanosoma cruzi CRT is highly immunogenic and exhibits cross-reactivity with isogenic cardiomyocytes, thus causing a local autoimmune reaction relevant to Chagas disease. 55 The observation that anti-CRT IgA or IgG serum levels did not significantly increase after anthracycline-based chemotherapy of breast cancer patients may reflect the inability of many tumors to translocate CRT to the cell surface, 56,57 defects in other hallmarks of ICD such as absent expression of HMGB1 (Yamazaki T et al, In Press), or deficient autophagy, 58 or the general irrelevance of humoral responses to clinical outcome. Future studies must correlate the therapyinduced raise in anti-CRT IgA antibodies or other immunological alterations, including changing frequencies in tumor antigen-specific T lymphocytes, with tumor cell-intrinsic, ICD-relevant parameters.…”

Section: Discussionmentioning

confidence: 99%

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

et al. 2013

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Immunogenic cell death induced by cytotoxic compounds contributes to the success of selected chemotherapies by eliciting a protective anticancer immune response, which is mediated by CD4 þ and CD8 þ T cells producing interferon-c. In many instances, cancer progression is associated with high titers of tumor-specific antibodies, which become detectable in the serum, but whose functional relevance is elusive. Here, we explored the role of humoral immune responses in the anticancer efficacy of anthracyclines. Chemotherapy reduced the number of tumor-infiltrating B cells, and failed to promote humoral responses against immunodominant tumor antigens. Although anthracycline-based anticancer chemotherapies failed in T cell-deficient mice, they successfully reduced the growth of cancers developing in mice lacking B lymphocytes (due to the injection of a B-celldepleting anti-CD20 antibody), immunoglobulins (Igs) or Ig receptors (Fc receptor) due to genetic manipulations. These results suggest that the humoral arm of antitumor immunity is dispensable for the immune-dependent therapeutic effect of anthracyclines against mouse sarcoma. In addition, we show here that the titers of IgA and IgG antibodies directed against an autoantigen appearing at the cell surface of tumor cells post chemotherapy (calreticulin, CRT) did not significantly increase in patients treated with anthracyclines, and that anti-CRT antibodies had no prognostic or predictive significance. Collectively, our data indicate that humoral anticancer immune responses differ from cellular responses in, thus far, that they do not contribute to the success of anthracycline-mediated anticancer therapies in human breast cancers and mouse sarcomas.

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“…Importantly, cytoplasts (enucleated cells) are as efficient in exposing CRT on their surface in response to anthracyclines as are intact cells, indicating that the critical lesion set by anthracyclines is cytoplasmic and does not involve a nuclear DNA damage response. 2 Although the mechanistic details of CRT/ERp57 translocation to the cell surface are unknown, it appears that caspase activation, 1,15 induction of an ER stress response 2 and actin cytoskeleton-dependent transport 16 are involved. Furthermore, as determined here by mutational analyses, the two proteins CRT and ERp57 are transported in a molecular complex that involves direct protein/protein interactions yet does not require the PDI activity of ERp57.…”

Section: Mtx (Figure 5cmentioning

confidence: 99%

“…The mechanisms through which CRT translocates to the PM surface are not known, although they involve caspase activation, an ER stress response leading to the phosphorylation of the eukaryotic initiation factor eIF2a, and active exocytosis. 1,15,16 The exact structure to which CRT binds on the surface is unknown, although it is plausible, based on its lectin activity, that it binds to carbohydrates of the glycocalix. The receptor of CRT on DC is also elusive, yet it might include scavenger receptor A, scavenger receptor expressed by endothelial cell-I, 17 CD91 18 or many other molecules such as CD40 ligand, TRAIL and Fas ligand.…”

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The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death

et al. 2008

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The exposure of calreticulin (CRT) on the plasma membrane can precede anthracycline-induced apoptosis and is required for cell death to be perceived as immunogenic. Mass spectroscopy, immunofluorescence and immunoprecipitation experiments revealed that CRT co-translocates to the surface with another endoplasmic reticulum-sessile protein, the disulfide isomerase ERp57. The knockout and knockdown of CRT or ERp57 inhibited the anthracycline-induced translocation of ERp57 or CRT, respectively. CRT point mutants that fail to interact with ERp57 were unable to restore ERp57 translocation upon transfection into crt À/À cells, underscoring that a direct interaction between CRT and ERp57 is strictly required for their co-translocation to the surface. ERp57 low tumor cells generated by retroviral introduction of an ERp57-specific shRNA exhibited a normal apoptotic response to anthracyclines in vitro, yet were resistant to anthracycline treatment in vivo. Moreover, ERp57 low cancer cells (which failed to expose CRT) treated with anthracyclines were unable to elicit an anti-tumor response in conditions in which control cells were highly immunogenic. The failure of ERp57 low cells to elicit immune responses and to respond to chemotherapy could be overcome by exogenous supply of recombinant CRT protein. These results indicate that tumors that possess an intrinsic defect in the CRT-translocating machinery become resistant to anthracycline chemotherapy due to their incapacity to elicit an anticancer immune response. The conventional treatment of cancer relies upon radiotherapy and chemotherapy, two procedures that supposedly mediate their therapeutic effects solely by intrinsic mechanisms of tumor cell death and without direct participation by the host immune system. Nevertheless, there are specific circumstances in which conventional anti-cancer treatments can induce a modality of cell death that is immunogenic, whereby dying cells elicit a tumor-specific immune response culminating in elimination of tumor cells. Although most chemotherapeutic agents kill tumor cells through a morphologically indistinguishable apoptotic pathway, they differ in their capacity to stimulate immunogenic as opposed to nonimmunogenic cell death. 1 Recently, we reported that tumor cells undergoing immunogenic cell death translocate intracellular calreticulin (endo-CRT) to their plasma membrane (PM) surface (ecto-CRT), facilitating tumor cell recognition and engulfment by dendritic cells (DC) and subsequent T-cellmediated elimination of the tumor. 2 Accordingly, anthracyclines and g-irradiation, which elicit immunogenic cell death, induce CRT exposure whereas other proapoptotic agents that induce non-immunogenic cell death fail to induce ecto-CRT. [2][3][4] Depletion of CRT abolishes the immunogenicity of cell death elicited by anthracyclines, whereas addition of exogenous CRT or enforced surface exposure of CRT by pharmacological agents that favor CRT translocation can enhance the immunogenicity of cell death. 2,4 An additional signal emitted during ...

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Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

Cited by 108 publications

References 42 publications

Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress

Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death

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