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PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway

Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitr...

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Autores principales: Elsayed, Abdelrahman M., Bayraktar, Emine, Amero, Paola, Salama, Salama A., Abdelaziz, Abdelaziz H., Ismail, Raed S., Zhang, Xinna, Ivan, Cristina, Sood, Anil K., Lopez-Berestein, Gabriel, Rodriguez-Aguayo, Cristian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918312/
https://www.ncbi.nlm.nih.gov/pubmed/33668685
http://dx.doi.org/10.3390/ijms22041882
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author Elsayed, Abdelrahman M.
Bayraktar, Emine
Amero, Paola
Salama, Salama A.
Abdelaziz, Abdelaziz H.
Ismail, Raed S.
Zhang, Xinna
Ivan, Cristina
Sood, Anil K.
Lopez-Berestein, Gabriel
Rodriguez-Aguayo, Cristian
author_facet Elsayed, Abdelrahman M.
Bayraktar, Emine
Amero, Paola
Salama, Salama A.
Abdelaziz, Abdelaziz H.
Ismail, Raed S.
Zhang, Xinna
Ivan, Cristina
Sood, Anil K.
Lopez-Berestein, Gabriel
Rodriguez-Aguayo, Cristian
author_sort Elsayed, Abdelrahman M.
collection PubMed
description Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2–specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.
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spelling pubmed-79183122021-03-02 PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway Elsayed, Abdelrahman M. Bayraktar, Emine Amero, Paola Salama, Salama A. Abdelaziz, Abdelaziz H. Ismail, Raed S. Zhang, Xinna Ivan, Cristina Sood, Anil K. Lopez-Berestein, Gabriel Rodriguez-Aguayo, Cristian Int J Mol Sci Article Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2–specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients. MDPI 2021-02-13 /pmc/articles/PMC7918312/ /pubmed/33668685 http://dx.doi.org/10.3390/ijms22041882 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Elsayed, Abdelrahman M.
Bayraktar, Emine
Amero, Paola
Salama, Salama A.
Abdelaziz, Abdelaziz H.
Ismail, Raed S.
Zhang, Xinna
Ivan, Cristina
Sood, Anil K.
Lopez-Berestein, Gabriel
Rodriguez-Aguayo, Cristian
PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway
title PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway
title_full PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway
title_fullStr PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway
title_full_unstemmed PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway
title_short PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway
title_sort prkar1b-as2 long noncoding rna promotes tumorigenesis, survival, and chemoresistance via the pi3k/akt/mtor pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918312/
https://www.ncbi.nlm.nih.gov/pubmed/33668685
http://dx.doi.org/10.3390/ijms22041882
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