TY - JOUR
T1 - Prkar1b-as2 long noncoding rna promotes tumorigenesis, survival, and chemoresistance via the pi3k/akt/mtor pathway
AU - Elsayed, Abdelrahman M.
AU - Bayraktar, Emine
AU - Amero, Paola
AU - Salama, Salama A.
AU - Abdelaziz, Abdelaziz H.
AU - Ismail, Raed S.
AU - Zhang, Xinna
AU - Ivan, Cristina
AU - Sood, Anil K.
AU - Lopez-Berestein, Gabriel
AU - Rodriguez-Aguayo, Cristian
N1 - Funding Information:
Funding: This work was supported in part by grants from the National Institutes of Health/National Cancer Institute (5U01CA213759-02, P30CA016672), American Cancer Society, and National Science Foundation (CHE-1411859) and an endowment grant from the John P. Gaines Foundation. Abdelrahman M. Elsayed was supported by a scholarship from the Egyptian Ministry of Higher Education. Cristian Rodriguez-Aguayo was supported by the National Institutes of Health through the Ovarian SPORE Career Enhancement Program and National Cancer Institute grant FP00000019.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/2/2
Y1 - 2021/2/2
N2 - 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 prolifer-ation, 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.
AB - 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 prolifer-ation, 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.
KW - AC147651.5
KW - Cisplatin resistance
KW - LncRNA
KW - Ovarian cancer
KW - PI3K/AKT/mTOR
KW - PRKAR1B-AS2
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UR - http://www.scopus.com/inward/citedby.url?scp=85100777533&partnerID=8YFLogxK
U2 - 10.3390/ijms22041882
DO - 10.3390/ijms22041882
M3 - Article
C2 - 33668685
AN - SCOPUS:85100777533
SN - 1661-6596
VL - 22
SP - 1
EP - 25
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 4
M1 - 1882
ER -