Mouse Cytotoxic T Cell-derived Granzyme B Activates the Mitochondrial Cell Death Pathway in a Bim-dependent Fashion

Catalán, Elena; Jaime-Sánchez, Paula; Aguiló, Nacho; Simon, Markus M.; Froelich, Christopher J.; Pardo, Julián

doi:10.1074/jbc.m114.631564

Cited by 23 publications

(21 citation statements)

References 42 publications

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“…77 GzmB primarily induces apoptosis via the intrinsic mitochondrial pathway by either cleaving Bid or activating Bim leading to the activation of Bak/Bax and subsequent generation of active Casp-3. 78 CM of co-culture hWJMSCs and NK cells secreted GzmB which induced apoptosis (Table 4), induced Bax gene expression (Table 5), this results was consistent with previous research that the several proteins that are involved in gzmB-induced apoptosis, including casp-9 and -3, Bim, Bid, Bak, Bax, and XIAP and Bcl-2 was not detected. Gzm B induced apoptosis cancer cells by inlvolving induction of p53 tumor suppressor gene.…”

Section: Effect CM From Co-culture Of Hwjmscs and Ils-nk Towards Pro-supporting

confidence: 91%

Direct and Indirect Effect of TNFα and IFNγ Toward Apoptosis in Breast Cancer Cells

Widowati

Jasaputra

Sumitro

et al. 2018

Mol Cell Biomed Sci

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Background: Breast cancer (BC) is the leading cause of death cancer in women. Cancer therapies using TNFα and IFNγ have been recently developed by direct effects and activation of immune responses. This study was performed to evaluate the effects of TNFα and IFNγ directly, and TNFα and IFNγ secreted by Conditioned Medium-human Wharton’s Jelly Mesenchymal Stem Cells (CM-hWJMSCs) toward apoptosis of BC cells (MCF7).Materials and Methods: BC cells were induced by TNFα and IFNγ in 175 and 350ng/mL, respectively. CM-hWJMSCs were produced by co-culture hWJMSCs and NK cells that secreted TNFα, IFNγ, perforin (Prf1), granzyme B (GzmB) for treating BC cells. The BC cells were treated with CM-hWJMSCs in 50%. The expression of apoptotic genes Bax, p53, and the antiapoptotic gene Bcl-2 were determined using RT-PCR.Results: TNFα and IFNγ at concentration of 350 ng/mL induced higher Bax expression compared to 175 ng/mL. TNFα and IFNγ 350 ng/mL, 175 ng/mL induced p53 expression, whilst TNFα and IFNγ at 350 ng/mL decreased Bcl-2 expression. Perf1, GzmB, TNFα and IFNγ-containing CM-hWJMSCs induced significantly apoptosis percentage, induced Bax expression, but did not effect p53, Bcl-2 expression.Conclusion: TNFα and IFNγ directly induce Bax, p53, decrease Bcl-2 gene expression. The Prf1, GzmB, TNFα, IFNγ-containing CM-hWJMSCs induce apoptosis and Bax expression.Keywords: breast cancer, Wharton’s Jelly mesenchymal stem cells, TNFα, IFNγ

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Section: Effect CM From Co-culture Of Hwjmscs and Ils-nk Towards Pro-supporting

confidence: 91%

Direct and Indirect Effect of TNFα and IFNγ Toward Apoptosis in Breast Cancer Cells

Widowati

Jasaputra

Sumitro

et al. 2018

Mol Cell Biomed Sci

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“…2). Notably, the mechanism of cell death activated by GZMB maybe dependent on the species (78) as well as on the type of cell transformation (96). In humans, it has been shown that cell cytotoxicity of cytokineactivated human NK cells is greatly reduced by inhibiting GZMB (97,98), confirming that GZMB is the main cell death inductor in CLs.…”

Section: Who Makes What During Cell Death Induced By Cls?mentioning

confidence: 74%

“…Indeed, GZMB has been shown to be crucial for CLmediated caspase-3 and Bid activation (93) and degradation of specific intracellular substrates such as tubulin (94,95), Mcl-1 (myeloid cell leukemia-1), or Bcl-x L (B-cell lymphoma-extra large; ref. 96). Importantly, these events occurred before membrane permeabilization could be detected (Fig.…”

Section: Who Makes What During Cell Death Induced By Cls?mentioning

confidence: 99%

How Do Cytotoxic Lymphocytes Kill Cancer Cells?

Martínez-Lostao

Anel

Pardo

2015

Clinical Cancer Research

Self Cite

586

439

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In the past few years, cancer immunotherapy has emerged as a safe and effective alternative for treatment of cancers that do not respond to classical treatments, including those types with high aggressiveness. New immune modulators, such as cytokines, blockers of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1(programmed cell death protein 1)/PD-L1 (programmed death-ligand 1), and interaction or adoptive cell therapy, have been developed and approved to treat solid and hematologic carcinomas. In these scenarios, cytotoxic lymphocytes (CL), mainly cytotoxic T cells (Tc) and natural killer (NK) cells, are ultimately responsible for killing the cancer cells and eradicating the tumor. Extensive studies have been conducted to assess how Tc and NK cells get activated and recognize the cancer cell. In contrast, few studies have focused on the effector molecules used by CLs to kill cancer cells during cancer immunosurveillance and immunotherapy. In this article, the two main pathways involved in CL-mediated tumor cell death, granule exocytosis (perforin and granzymes) and death ligands, are briefly introduced, followed by a critical discussion of the molecules involved in cell death during cancer immunosurveillance and immunotherapy. This discussion also covers unexpected consequences of proinflammatory and survival effects of granzymes and death ligands and recent experimental evidence indicating that perforin and granzymes of CLs can activate nonapoptotic pathways of cell death, overcoming apoptosis defects and chemoresistance. The consequences of apoptosis versus other modalities of cell death for an effective treatment of cancer by modulating the patient immune system are also briefly discussed.

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“…Additionally, NK-cells' granules can also contain granzyme-M [56]. While granzyme-B can directly activate effector caspases-3 and -7, it preferentially mediates target cell killing by activating the intrinsic pathway of apoptosis through the cleavage of BIM and/or BID [57][58][59].…”

Section: Apoptosis the Main Mechanism Of Immune Cell-mediated Tumor mentioning

confidence: 99%

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Holthof

Mutis

2020

Cancers

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The power of immunotherapy in the battle of Multiple Myeloma (MM) started with allogeneic stem cell transplantation, and was rediscovered with immunomodulatory drugs and extended with the outstanding results achieved with targeted antibodies. Today, next to powerful antibodies Elotuzumab and Daratumumab, several T-cell-based immunotherapeutic approaches, such as bispecific antibodies and chimeric antigen receptor-transduced T-cells (CAR T-cells) are making their successful entry in the immunotherapy arena with highly promising results in clinical trials. Nonetheless, similar to what is observed in chemotherapy, MM appears capable to escape from immunotherapy, especially through tight interactions with the cells of the bone marrow microenvironment (BM-ME). This review will outline our current understanding on how BM-ME protects MM-cells from immunotherapy through immunosuppression and through induction of intrinsic resistance against cytotoxic effector mechanisms of T- and NK-cells.

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Mouse Cytotoxic T Cell-derived Granzyme B Activates the Mitochondrial Cell Death Pathway in a Bim-dependent Fashion

Cited by 23 publications

References 42 publications

Direct and Indirect Effect of TNFα and IFNγ Toward Apoptosis in Breast Cancer Cells

Direct and Indirect Effect of TNFα and IFNγ Toward Apoptosis in Breast Cancer Cells

How Do Cytotoxic Lymphocytes Kill Cancer Cells?

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

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