Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1783657894157221888 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7918312 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT elsayedabdelrahmanm prkar1bas2longnoncodingrnapromotestumorigenesissurvivalandchemoresistanceviathepi3kaktmtorpathway AT bayraktaremine prkar1bas2longnoncodingrnapromotestumorigenesissurvivalandchemoresistanceviathepi3kaktmtorpathway AT ameropaola prkar1bas2longnoncodingrnapromotestumorigenesissurvivalandchemoresistanceviathepi3kaktmtorpathway AT salamasalamaa prkar1bas2longnoncodingrnapromotestumorigenesissurvivalandchemoresistanceviathepi3kaktmtorpathway AT abdelazizabdelazizh prkar1bas2longnoncodingrnapromotestumorigenesissurvivalandchemoresistanceviathepi3kaktmtorpathway AT ismailraeds prkar1bas2longnoncodingrnapromotestumorigenesissurvivalandchemoresistanceviathepi3kaktmtorpathway AT zhangxinna prkar1bas2longnoncodingrnapromotestumorigenesissurvivalandchemoresistanceviathepi3kaktmtorpathway AT ivancristina prkar1bas2longnoncodingrnapromotestumorigenesissurvivalandchemoresistanceviathepi3kaktmtorpathway AT soodanilk prkar1bas2longnoncodingrnapromotestumorigenesissurvivalandchemoresistanceviathepi3kaktmtorpathway AT lopezberesteingabriel prkar1bas2longnoncodingrnapromotestumorigenesissurvivalandchemoresistanceviathepi3kaktmtorpathway AT rodriguezaguayocristian prkar1bas2longnoncodingrnapromotestumorigenesissurvivalandchemoresistanceviathepi3kaktmtorpathway |