Gamma Radiation-Attenuated  Toxoplasma gondii  Provokes Apoptosis in Ehrlich Ascites Carcinoma-Bearing Mice Generating Long-Lasting Immunity

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Abstract

Purpose:

Pathological angiogenesis and apoptosis evasions are common hallmarks of cancer. A different approach to the antitumor effect of parasitic diseases caused by certain protozoans and helminthes had been adopted in recent years as they can affect many cancer characteristics. The present work is an attempt to assess the effect of gamma radiation-attenuated Toxoplasma gondii ME49 as an antiapoptotic and angiogenic regulator modifier on tumor growth aimed at improving cancer protective protocols.

Methods:

Attenuated Toxoplasma gondii ME49 was administered orally to mice 2 weeks before inoculation with Ehrlich ascites carcinoma to allow stimulation of the immune response. Hepatic histopathology and immune responses were determined for each group.

Results:

Marked suppression of the tumor proliferation with induction of long-lasting immunity by stimulating interferon γ and downregulating transforming growth factor β. The level of tumor promoting inflammatory markers (STAT-3 and tumor necrosis factor α), the angiogenic factors (vascular endothelial growth factor A, integrin, and matrix metallopeptidase 2 and matrix metallopeptidase 9), as well as nitric oxide concentration were significantly decreased. This was collimated with an improvement in apoptotic regulators (cytochrome-c, Bax, Bak, and caspase 3) in liver tissues of vaccinated mice group compared to Ehrlich ascites carcinoma-bearing one. Moreover, the histopathological investigations confirmed this improvement.

Conclusion:

Hence, there is an evidence of potency of radiation attenuated Toxoplasma vaccine in immune activation and targeting tumor cell that can be used as a prophylactic or an adjuvant in combination with chemotherapeutic drugs.

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Most cited references 48

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STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells.

Joo Jung, Hyun Lee, Ik Hyun Cho … (2005)

Aberrantly enhanced vascular endothelial growth factor (VEGF) gene expression is associated with increased tumor growth and metastatic spread of solid malignancies, including human renal carcinomas. Persistent activation of STAT3 is linked to tumor-associated angiogenesis, but underlying mechanisms remain unclear. Therefore, we examined whether STAT3 modulates the stability and activity of hypoxia-inducible factor-1alpha (HIF-1alpha), and in turn enhances VEGF expression. We found that STAT3 was activated in ischemic rat kidneys and hypoxic human renal carcinoma cells. We also found that hypoxia-induced activation of STAT3 transactivated the VEGF promoter and increased the expression of VEGF transcripts. Consistent with these findings, STAT3 inhibition attenuated the hypoxic induction of VEGF. Interestingly, activated STAT3 increased HIF-1alpha protein levels due to the HIF-1alpha stability by blocking HIF-1alpha degradation and accelerated its de novo synthesis. The novel interaction of STAT3 with HIF-1alpha was identified in hypoxic renal carcinoma cells. Furthermore, hypoxia recruited STAT3, HIF-1alpha, and p300 to the VEGF promoter and induced histone H3 acetylation. Therefore, these findings provide compelling evidence that a causal relationship exists between STAT3 activation and HIF-1-dependent angiogenesis and suggest that therapeutic modalities designed to disrupt STAT3 signaling hold considerable promise for the blocking tumor growth and enhancing apoptosis of cancer cells and tissues.

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Interferon gamma in cancer immunotherapy

Ling Ni, Jian Liang Lu (2018)

Abstract Immune system can recognize self vs transformed self. That is why cancer immunotherapy achieves notable benefits in a wide variety of cancers. Recently, several papers reported that immune checkpoint blockade therapy led to upregulation of IFNγ and in turn clearance of tumor cells. In this review, we conducted an extensive literature search of recent 5‐year studies about the roles of IFNγ signaling in both tumor immune surveillance and immune evasion. In addition to well‐known functions, IFNγ signaling also induces tumor ischemia and homeostasis program, resulting in tumor clearance and tumor escape, respectively. The yin and the yang of IFNγ signaling are summarized. Thus, this review helps us to comprehensively understand the roles of IFNγ in tumor immunity, which contributes to better design and management of clinical immunotherapy approaches.

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Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis.

A. Gross, J Jockel, M Wei … (1998)

Expression of the pro-apoptotic molecule BAX has been shown to induce cell death. While BAX forms both homo- and heterodimers, questions remain concerning its native conformation in vivo and which moiety is functionally active. Here we demonstrate that a physiologic death stimulus, the withdrawal of interleukin-3 (IL-3), resulted in the translocation of monomeric BAX from the cytosol to the mitochondria where it could be cross-linked as a BAX homodimer. In contrast, cells protected by BCL-2 demonstrated a block in this process in that BAX did not redistribute or homodimerize in response to a death signal. To test the functional consequence of BAX dimerization, we expressed a chimeric FKBP-BAX molecule. Enforced dimerization of FKBP-BAX by the bivalent ligand FK1012 resulted in its translocation to mitochondria and induced apoptosis. Caspases were activated yet caspase inhibitors did not block death; cytochrome c was not released detectably despite the induction of mitochondrial dysfunction. Moreover, enforced dimerization of BAX overrode the protection by BCL-XL and IL-3 to kill cells. These data support a model in which a death signal results in the activation of BAX. This conformational change in BAX manifests in its translocation, mitochondrial membrane insertion and homodimerization, and a program of mitochondrial dysfunction that results in cell death.

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Author and article information

Journal

Journal ID (nlm-ta): Technol Cancer Res Treat

Journal ID (iso-abbrev): Technol. Cancer Res. Treat

Journal ID (publisher-id): TCT

Journal ID (hwp): sptct

Title: Technology in Cancer Research & Treatment

Publisher: SAGE Publications (Sage CA: Los Angeles, CA )

ISSN (Print): 1533-0346

ISSN (Electronic): 1533-0338

Publication date (Electronic): 22 June 2020

Publication date Collection: 2020

Volume: 19

Electronic Location Identifier: 1533033820926593

Affiliations

[1 ]Health Radiation Research Department, National Center for Radiation Research and Technology (NCRRT)-Atomic Energy Authority (AEA), Cairo, Egypt

[2 ]Radiation Biology Department, National Center for Radiation Research and Technology, Atomic Energy authority, Cairo, Egypt

Author notes

[*]Nermeen M. Elbakary, Radiation Biology Department, National Center for Radiation Research and Technology, Atomic Energy authority, 3 Ahmed Al Zomor St, Al Zohour Sector, Cairo 11787, Egypt. Email: nermeen_ahmed11@ 123456yahoo.com

Author information

Nermeen M. Elbakary https://orcid.org/0000-0002-0128-3159

Article

Publisher ID: 10.1177_1533033820926593

DOI: 10.1177/1533033820926593

PMC ID: 7309383

PubMed ID: 32567499

SO-VID: dcca5638-8aa5-494a-a82c-78736d15e219

License:

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 30 January 2020

Date revision received : 27 March 2020

Date accepted : 16 April 2020

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cover-date January-December 2020

typesetter ts3

Keywords: toxoplasma gondii,gamma radiation,ifn-γ,stat-3,vegf-a,angiogenic,apoptotic regulator

Data availability:

Keywords: toxoplasma gondii, gamma radiation, ifn-γ, stat-3, vegf-a, angiogenic, apoptotic regulator

Gamma Radiation-Attenuated Toxoplasma gondii Provokes Apoptosis in Ehrlich Ascites Carcinoma-Bearing Mice Generating Long-Lasting Immunity

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Most cited references 48

STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells.

Interferon gamma in cancer immunotherapy

Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis.

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