Cargando…

Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer

Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the bric-a-brac-tramtrack-broad complex/pox virus and zinc finger gene family, is known to serve important roles in the proliferation and growth of tumor cells, and in chemotherapy resistance. However, the underlying molecular mechanisms thro...

Descripción completa

Detalles Bibliográficos
Autores principales: Nakayama, Kentaro, Rahman, Munmun, Rahman, Mohammed Tanjimur, Nakamura, Kohei, Sato, Emi, Katagiri, Hiroshi, Ishibashi, Tomoka, Ishikawa, Masako, Iida, Kouji, Razia, Sultana, Ishikawa, Noriyuki, Kyo, Satoru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453174/
https://www.ncbi.nlm.nih.gov/pubmed/28599472
http://dx.doi.org/10.3892/ol.2017.6099
_version_ 1783240595111673856
author Nakayama, Kentaro
Rahman, Munmun
Rahman, Mohammed Tanjimur
Nakamura, Kohei
Sato, Emi
Katagiri, Hiroshi
Ishibashi, Tomoka
Ishikawa, Masako
Iida, Kouji
Razia, Sultana
Ishikawa, Noriyuki
Kyo, Satoru
author_facet Nakayama, Kentaro
Rahman, Munmun
Rahman, Mohammed Tanjimur
Nakamura, Kohei
Sato, Emi
Katagiri, Hiroshi
Ishibashi, Tomoka
Ishikawa, Masako
Iida, Kouji
Razia, Sultana
Ishikawa, Noriyuki
Kyo, Satoru
author_sort Nakayama, Kentaro
collection PubMed
description Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the bric-a-brac-tramtrack-broad complex/pox virus and zinc finger gene family, is known to serve important roles in the proliferation and growth of tumor cells, and in chemotherapy resistance. However, the underlying molecular mechanisms through which NAC1 contributes to drug resistance remain unclear. In the present study, the role of NAC1 in drug resistance in ovarian cancer was investigated. NAC1 expression was markedly negatively associated with growth arrest and DNA-damage-inducible 45γ-interacting protein 1 (GADD45GIP1) expression in ovarian cancer. Increased NAC1 expression or decreased GADD45GIP1 expression was significantly associated with decreased progression-free survival (P=0.0041). Multivariate analysis demonstrated that NAC1/GADD45GIP1 expression was an independent prognostic factor of progression-free survival (P=0.0405). It was investigated whether cellular senescence was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. Treatment with cisplatin activated cellular senescence in ovarian cancer cell lines (SKOV3 and TOV-21G cells). Furthermore, knockdown of NAC1 by RNA interference significantly increased GADD45GIP1 expression and inhibited cisplatin-induced cellular senescence, resulting in increased cisplatin cytotoxicity in SKOV3 cells, which express increased levels of NAC1. To investigate whether the sensitizing effect of NAC1 inhibition on cisplatin-induced cytotoxicity may be attributed to the suppression of cellular senescence, the effects of NAC1 overexpression were assessed in TOV-21G cells, which do not express endogenous NAC1. Transfection with NAC1 in TOV-21G cells reduced the sensitivity of TOV-21G cells to cisplatin, indicating that suppression of cellular senescence was induced by GADD45GP1 activation. The results of the present study suggest that NAC1 is a negative regulator of cellular senescence and that NAC1-dependent suppression of senescence, mediated through GADD45GIP1, serves an important role in promoting cisplatin resistance. Therefore, the NAC1/GADD45GIP1 axis may be a potential target for the treatment of ovarian cancer, particularly in platinum-resistant cancers.
format Online
Article
Text
id pubmed-5453174
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher D.A. Spandidos
record_format MEDLINE/PubMed
spelling pubmed-54531742017-06-08 Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer Nakayama, Kentaro Rahman, Munmun Rahman, Mohammed Tanjimur Nakamura, Kohei Sato, Emi Katagiri, Hiroshi Ishibashi, Tomoka Ishikawa, Masako Iida, Kouji Razia, Sultana Ishikawa, Noriyuki Kyo, Satoru Oncol Lett Articles Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the bric-a-brac-tramtrack-broad complex/pox virus and zinc finger gene family, is known to serve important roles in the proliferation and growth of tumor cells, and in chemotherapy resistance. However, the underlying molecular mechanisms through which NAC1 contributes to drug resistance remain unclear. In the present study, the role of NAC1 in drug resistance in ovarian cancer was investigated. NAC1 expression was markedly negatively associated with growth arrest and DNA-damage-inducible 45γ-interacting protein 1 (GADD45GIP1) expression in ovarian cancer. Increased NAC1 expression or decreased GADD45GIP1 expression was significantly associated with decreased progression-free survival (P=0.0041). Multivariate analysis demonstrated that NAC1/GADD45GIP1 expression was an independent prognostic factor of progression-free survival (P=0.0405). It was investigated whether cellular senescence was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. Treatment with cisplatin activated cellular senescence in ovarian cancer cell lines (SKOV3 and TOV-21G cells). Furthermore, knockdown of NAC1 by RNA interference significantly increased GADD45GIP1 expression and inhibited cisplatin-induced cellular senescence, resulting in increased cisplatin cytotoxicity in SKOV3 cells, which express increased levels of NAC1. To investigate whether the sensitizing effect of NAC1 inhibition on cisplatin-induced cytotoxicity may be attributed to the suppression of cellular senescence, the effects of NAC1 overexpression were assessed in TOV-21G cells, which do not express endogenous NAC1. Transfection with NAC1 in TOV-21G cells reduced the sensitivity of TOV-21G cells to cisplatin, indicating that suppression of cellular senescence was induced by GADD45GP1 activation. The results of the present study suggest that NAC1 is a negative regulator of cellular senescence and that NAC1-dependent suppression of senescence, mediated through GADD45GIP1, serves an important role in promoting cisplatin resistance. Therefore, the NAC1/GADD45GIP1 axis may be a potential target for the treatment of ovarian cancer, particularly in platinum-resistant cancers. D.A. Spandidos 2017-06 2017-04-26 /pmc/articles/PMC5453174/ /pubmed/28599472 http://dx.doi.org/10.3892/ol.2017.6099 Text en Copyright: © Nakayama et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Nakayama, Kentaro
Rahman, Munmun
Rahman, Mohammed Tanjimur
Nakamura, Kohei
Sato, Emi
Katagiri, Hiroshi
Ishibashi, Tomoka
Ishikawa, Masako
Iida, Kouji
Razia, Sultana
Ishikawa, Noriyuki
Kyo, Satoru
Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer
title Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer
title_full Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer
title_fullStr Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer
title_full_unstemmed Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer
title_short Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer
title_sort nucleus accumbens-1/gadd45gip1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453174/
https://www.ncbi.nlm.nih.gov/pubmed/28599472
http://dx.doi.org/10.3892/ol.2017.6099
work_keys_str_mv AT nakayamakentaro nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer
AT rahmanmunmun nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer
AT rahmanmohammedtanjimur nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer
AT nakamurakohei nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer
AT satoemi nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer
AT katagirihiroshi nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer
AT ishibashitomoka nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer
AT ishikawamasako nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer
AT iidakouji nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer
AT raziasultana nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer
AT ishikawanoriyuki nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer
AT kyosatoru nucleusaccumbens1gadd45gip1axismediatescisplatinresistancethroughcellularsenescenceinovariancancer