CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells.

Malignant pleural mesothelioma (MPM) is an asbestos-related thoracic malignancy that is characterized by late metastases, and resistance to therapeutic modalities. The toxic side-effects of MPM therapies often limit their clinical effectiveness, thus necessitating development of new agents to effect...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Shazia Jamal, Vino T Cheriyan, Magesh Muthu, Sara Munie, Edi Levi, Abdelkader E Ashour, Harvey I Pass, Anil Wali, Mandip Singh, Arun K Rishi
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2014
Materias:
R
Q
Acceso en línea:https://doaj.org/article/f40d635b267c4d139155c3e53e35e55b
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:f40d635b267c4d139155c3e53e35e55b
record_format dspace
spelling oai:doaj.org-article:f40d635b267c4d139155c3e53e35e55b2021-11-18T08:29:42ZCARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells.1932-620310.1371/journal.pone.0089146https://doaj.org/article/f40d635b267c4d139155c3e53e35e55b2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24598827/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Malignant pleural mesothelioma (MPM) is an asbestos-related thoracic malignancy that is characterized by late metastases, and resistance to therapeutic modalities. The toxic side-effects of MPM therapies often limit their clinical effectiveness, thus necessitating development of new agents to effectively treat and manage this disease in clinic. CARP-1 functional mimetics (CFMs) are a novel class of compounds that inhibit growth of diverse cancer cell types. Here we investigated MPM cell growth suppression by the CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited MPM cell growth, in vitro, in part by stimulating apoptosis. Apoptosis by CFM-4 involved activation of pro-apoptotic stress-activated protein kinases (SAPKs) p38 and JNK, elevated CARP-1 expression, cleavage of PARP1, and loss of the oncogene c-myc as well as mitotic cyclin B1. Treatments of MPM cells with CFM-4 resulted in depletion of NF-κB signaling inhibitor ABIN1 and Inhibitory κB (IκB)α and β, while increasing expression of pro-apoptotic death receptor (DR) 4 protein. CFM-4 enhanced expression of serine-phosphorylated podoplanin and cleavage of vimetin. CFMs also attenuated biological properties of the MPM cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Both podoplanin and vimentin regulate processes of cell motility and invasion, and their expression often correlates with metastatic disease, and poor prognosis. The fact that phosphorylation of serines in the cytoplasmic domain of podoplanin interferes with processes of cellular motility, CFM-4-dependent elevated phosphorylated podoplanin and cleavage of vimentin underscore a metastasis inhibitory property of these compounds, and suggest that CFMs and/or their future analogs have potential as anti-MPM agents.Shazia JamalVino T CheriyanMagesh MuthuSara MunieEdi LeviAbdelkader E AshourHarvey I PassAnil WaliMandip SinghArun K RishiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 3, p e89146 (2014)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Shazia Jamal
Vino T Cheriyan
Magesh Muthu
Sara Munie
Edi Levi
Abdelkader E Ashour
Harvey I Pass
Anil Wali
Mandip Singh
Arun K Rishi
CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells.
description Malignant pleural mesothelioma (MPM) is an asbestos-related thoracic malignancy that is characterized by late metastases, and resistance to therapeutic modalities. The toxic side-effects of MPM therapies often limit their clinical effectiveness, thus necessitating development of new agents to effectively treat and manage this disease in clinic. CARP-1 functional mimetics (CFMs) are a novel class of compounds that inhibit growth of diverse cancer cell types. Here we investigated MPM cell growth suppression by the CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited MPM cell growth, in vitro, in part by stimulating apoptosis. Apoptosis by CFM-4 involved activation of pro-apoptotic stress-activated protein kinases (SAPKs) p38 and JNK, elevated CARP-1 expression, cleavage of PARP1, and loss of the oncogene c-myc as well as mitotic cyclin B1. Treatments of MPM cells with CFM-4 resulted in depletion of NF-κB signaling inhibitor ABIN1 and Inhibitory κB (IκB)α and β, while increasing expression of pro-apoptotic death receptor (DR) 4 protein. CFM-4 enhanced expression of serine-phosphorylated podoplanin and cleavage of vimetin. CFMs also attenuated biological properties of the MPM cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Both podoplanin and vimentin regulate processes of cell motility and invasion, and their expression often correlates with metastatic disease, and poor prognosis. The fact that phosphorylation of serines in the cytoplasmic domain of podoplanin interferes with processes of cellular motility, CFM-4-dependent elevated phosphorylated podoplanin and cleavage of vimentin underscore a metastasis inhibitory property of these compounds, and suggest that CFMs and/or their future analogs have potential as anti-MPM agents.
format article
author Shazia Jamal
Vino T Cheriyan
Magesh Muthu
Sara Munie
Edi Levi
Abdelkader E Ashour
Harvey I Pass
Anil Wali
Mandip Singh
Arun K Rishi
author_facet Shazia Jamal
Vino T Cheriyan
Magesh Muthu
Sara Munie
Edi Levi
Abdelkader E Ashour
Harvey I Pass
Anil Wali
Mandip Singh
Arun K Rishi
author_sort Shazia Jamal
title CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells.
title_short CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells.
title_full CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells.
title_fullStr CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells.
title_full_unstemmed CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells.
title_sort carp-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells.
publisher Public Library of Science (PLoS)
publishDate 2014
url https://doaj.org/article/f40d635b267c4d139155c3e53e35e55b
work_keys_str_mv AT shaziajamal carp1functionalmimeticsareanovelclassofsmallmoleculeinhibitorsofmalignantpleuralmesotheliomacells
AT vinotcheriyan carp1functionalmimeticsareanovelclassofsmallmoleculeinhibitorsofmalignantpleuralmesotheliomacells
AT mageshmuthu carp1functionalmimeticsareanovelclassofsmallmoleculeinhibitorsofmalignantpleuralmesotheliomacells
AT saramunie carp1functionalmimeticsareanovelclassofsmallmoleculeinhibitorsofmalignantpleuralmesotheliomacells
AT edilevi carp1functionalmimeticsareanovelclassofsmallmoleculeinhibitorsofmalignantpleuralmesotheliomacells
AT abdelkadereashour carp1functionalmimeticsareanovelclassofsmallmoleculeinhibitorsofmalignantpleuralmesotheliomacells
AT harveyipass carp1functionalmimeticsareanovelclassofsmallmoleculeinhibitorsofmalignantpleuralmesotheliomacells
AT anilwali carp1functionalmimeticsareanovelclassofsmallmoleculeinhibitorsofmalignantpleuralmesotheliomacells
AT mandipsingh carp1functionalmimeticsareanovelclassofsmallmoleculeinhibitorsofmalignantpleuralmesotheliomacells
AT arunkrishi carp1functionalmimeticsareanovelclassofsmallmoleculeinhibitorsofmalignantpleuralmesotheliomacells
_version_ 1718421778827575296