Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma

Abstract Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves c...

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Autores principales:	Mario Cioce, Claudia Canino, Harvey Pass, Giovanni Blandino, Sabrina Strano, Vito Michele Fazio
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Arachidonic acid cPLA2 NFkB Chemoresistance ALDH Spheroids Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/c87f2a9f8aa34141ad564cf7c176bf72
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spelling	oai:doaj.org-article:c87f2a9f8aa34141ad564cf7c176bf722021-11-08T10:44:44ZArachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma10.1186/s13046-021-02118-y1756-9966https://doaj.org/article/c87f2a9f8aa34141ad564cf7c176bf722021-11-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02118-yhttps://doaj.org/toc/1756-9966Abstract Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves complex rearrangements of the MPM secretome, mediated by the acquisition of a senescence-associated-secretory-phenotype (SASP). This fuels the emergence of chemoresistant cell subpopulations, with specific gene expression traits and protumorigenic features. The SASP-driven rearrangement of MPM secretome takes days to weeks to occur. Thus, we have searched for early mediators of such adaptive process and focused on metabolites differentially released in mesothelioma vs mesothelial cell culture media, after treatment with pemetrexed. Methods Mass spectrometry-based (LC/MS and GC/MS) identification of extracellular metabolites and unbiased statistical analysis were performed on the spent media of mesothelial and mesothelioma cell lines, at steady state and after a pulse with pharmacologically relevant doses of the drug. ELISA based evaluation of arachidonic acid (AA) levels and enzyme inhibition assays were used to explore the role of cPLA2 in AA release and that of LOX/COX-mediated processing of AA. QRT-PCR, flow cytometry analysis of ALDH expressing cells and 3D spheroid growth assays were employed to assess the role of AA at mediating chemoresistance features of MPM. ELISA based detection of p65 and IkBalpha were used to interrogate the NFkB pathway activation in AA-treated cells. Results We first validated what is known or expected from the mechanism of action of the antifolate. Further, we found increased levels of PUFAs and, more specifically, arachidonic acid (AA), in the transformed cell lines treated with pemetrexed. We showed that pharmacologically relevant doses of AA tightly recapitulated the rearrangement of cell subpopulations and the gene expression changes happening in pemetrexed -treated cultures and related to chemoresistance. Further, we showed that release of AA following pemetrexed treatment was due to cPLA2 and that AA signaling impinged on NFkB activation and largely affected anchorage-independent, 3D growth and the resistance of the MPM 3D cultures to the drug. Conclusions AA is an early mediator of the adaptive response to pem in chemoresistant MPM and, possibly, other malignancies.Mario CioceClaudia CaninoHarvey PassGiovanni BlandinoSabrina StranoVito Michele FazioBMCarticleArachidonic acidcPLA2NFkBChemoresistanceALDHSpheroidsNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arachidonic acid cPLA2 NFkB Chemoresistance ALDH Spheroids Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Arachidonic acid cPLA2 NFkB Chemoresistance ALDH Spheroids Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Mario Cioce Claudia Canino Harvey Pass Giovanni Blandino Sabrina Strano Vito Michele Fazio Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma
description	Abstract Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves complex rearrangements of the MPM secretome, mediated by the acquisition of a senescence-associated-secretory-phenotype (SASP). This fuels the emergence of chemoresistant cell subpopulations, with specific gene expression traits and protumorigenic features. The SASP-driven rearrangement of MPM secretome takes days to weeks to occur. Thus, we have searched for early mediators of such adaptive process and focused on metabolites differentially released in mesothelioma vs mesothelial cell culture media, after treatment with pemetrexed. Methods Mass spectrometry-based (LC/MS and GC/MS) identification of extracellular metabolites and unbiased statistical analysis were performed on the spent media of mesothelial and mesothelioma cell lines, at steady state and after a pulse with pharmacologically relevant doses of the drug. ELISA based evaluation of arachidonic acid (AA) levels and enzyme inhibition assays were used to explore the role of cPLA2 in AA release and that of LOX/COX-mediated processing of AA. QRT-PCR, flow cytometry analysis of ALDH expressing cells and 3D spheroid growth assays were employed to assess the role of AA at mediating chemoresistance features of MPM. ELISA based detection of p65 and IkBalpha were used to interrogate the NFkB pathway activation in AA-treated cells. Results We first validated what is known or expected from the mechanism of action of the antifolate. Further, we found increased levels of PUFAs and, more specifically, arachidonic acid (AA), in the transformed cell lines treated with pemetrexed. We showed that pharmacologically relevant doses of AA tightly recapitulated the rearrangement of cell subpopulations and the gene expression changes happening in pemetrexed -treated cultures and related to chemoresistance. Further, we showed that release of AA following pemetrexed treatment was due to cPLA2 and that AA signaling impinged on NFkB activation and largely affected anchorage-independent, 3D growth and the resistance of the MPM 3D cultures to the drug. Conclusions AA is an early mediator of the adaptive response to pem in chemoresistant MPM and, possibly, other malignancies.
format	article
author	Mario Cioce Claudia Canino Harvey Pass Giovanni Blandino Sabrina Strano Vito Michele Fazio
author_facet	Mario Cioce Claudia Canino Harvey Pass Giovanni Blandino Sabrina Strano Vito Michele Fazio
author_sort	Mario Cioce
title	Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma
title_short	Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma
title_full	Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma
title_fullStr	Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma
title_full_unstemmed	Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma
title_sort	arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma
publisher	BMC
publishDate	2021
url	https://doaj.org/article/c87f2a9f8aa34141ad564cf7c176bf72
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Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma

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