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Distinct mechanism of cervical cancer cell death caused by the investigational new drug SHetA2

Drug-targetable vulnerabilities of cancer cells include their dependence on heat shock proteins (HSPs) to support elevated mitochondrial metabolism and counteract cell death factors. The investigational new drug SHetA2 targets these vulnerabilities in ovarian and endometrial cancer cells by disrupti...

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Autores principales: Rai, Rajani, Chandra, Vishal, Kennedy, Amy L., Zuna, Rosemary E., Benbrook, Doris Mangiaracina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531157/
https://www.ncbi.nlm.nih.gov/pubmed/36203464
http://dx.doi.org/10.3389/fonc.2022.958536
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author Rai, Rajani
Chandra, Vishal
Kennedy, Amy L.
Zuna, Rosemary E.
Benbrook, Doris Mangiaracina
author_facet Rai, Rajani
Chandra, Vishal
Kennedy, Amy L.
Zuna, Rosemary E.
Benbrook, Doris Mangiaracina
author_sort Rai, Rajani
collection PubMed
description Drug-targetable vulnerabilities of cancer cells include their dependence on heat shock proteins (HSPs) to support elevated mitochondrial metabolism and counteract cell death factors. The investigational new drug SHetA2 targets these vulnerabilities in ovarian and endometrial cancer cells by disrupting complexes of the mortalin HSP with its client proteins (mitochondrial support proteins, metabolic enzymes, p53) leading to mitochondrial leakage of cytochrome c and apoptosis-inducing factor (AIF), and caspase-dependent apoptosis. Our objective was to evaluate the roles of mitochondrial damage and another SHetA2-target HSP protein, cytoplasmic heat shock cognate 70 (hsc70), in the mechanism of SHetA2 killing of cervical cancer cells. Cervical cancer cells responded to SHetA2 with excessive mitophagy that did not deter AIF leakage into the cytoplasm. Then, hsc70 was unable to prevent cytoplasmic AIF nuclear translocation and promotion of DNA damage and cell death, because SHetA2 disrupted hsc70/AIF complexes. The Cancer Genome Atlas analysis found that overexpression of hsc70, but not mortalin, was associated with worse cervical cancer patient survival. Use of specific inhibitors documented that AIF and mitophagy, but not caspases, contributed to the mechanism of SHetA2-induced cell death in cervical cancer cells. As validation, excessive mitophagy and lack of caspase activation were observed in SHetA2-inhibited xenograft tumors.
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spelling pubmed-95311572022-10-05 Distinct mechanism of cervical cancer cell death caused by the investigational new drug SHetA2 Rai, Rajani Chandra, Vishal Kennedy, Amy L. Zuna, Rosemary E. Benbrook, Doris Mangiaracina Front Oncol Oncology Drug-targetable vulnerabilities of cancer cells include their dependence on heat shock proteins (HSPs) to support elevated mitochondrial metabolism and counteract cell death factors. The investigational new drug SHetA2 targets these vulnerabilities in ovarian and endometrial cancer cells by disrupting complexes of the mortalin HSP with its client proteins (mitochondrial support proteins, metabolic enzymes, p53) leading to mitochondrial leakage of cytochrome c and apoptosis-inducing factor (AIF), and caspase-dependent apoptosis. Our objective was to evaluate the roles of mitochondrial damage and another SHetA2-target HSP protein, cytoplasmic heat shock cognate 70 (hsc70), in the mechanism of SHetA2 killing of cervical cancer cells. Cervical cancer cells responded to SHetA2 with excessive mitophagy that did not deter AIF leakage into the cytoplasm. Then, hsc70 was unable to prevent cytoplasmic AIF nuclear translocation and promotion of DNA damage and cell death, because SHetA2 disrupted hsc70/AIF complexes. The Cancer Genome Atlas analysis found that overexpression of hsc70, but not mortalin, was associated with worse cervical cancer patient survival. Use of specific inhibitors documented that AIF and mitophagy, but not caspases, contributed to the mechanism of SHetA2-induced cell death in cervical cancer cells. As validation, excessive mitophagy and lack of caspase activation were observed in SHetA2-inhibited xenograft tumors. Frontiers Media S.A. 2022-09-20 /pmc/articles/PMC9531157/ /pubmed/36203464 http://dx.doi.org/10.3389/fonc.2022.958536 Text en Copyright © 2022 Rai, Chandra, Kennedy, Zuna and Benbrook https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Rai, Rajani
Chandra, Vishal
Kennedy, Amy L.
Zuna, Rosemary E.
Benbrook, Doris Mangiaracina
Distinct mechanism of cervical cancer cell death caused by the investigational new drug SHetA2
title Distinct mechanism of cervical cancer cell death caused by the investigational new drug SHetA2
title_full Distinct mechanism of cervical cancer cell death caused by the investigational new drug SHetA2
title_fullStr Distinct mechanism of cervical cancer cell death caused by the investigational new drug SHetA2
title_full_unstemmed Distinct mechanism of cervical cancer cell death caused by the investigational new drug SHetA2
title_short Distinct mechanism of cervical cancer cell death caused by the investigational new drug SHetA2
title_sort distinct mechanism of cervical cancer cell death caused by the investigational new drug sheta2
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531157/
https://www.ncbi.nlm.nih.gov/pubmed/36203464
http://dx.doi.org/10.3389/fonc.2022.958536
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