NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction

NVP-BKM120, a potent and highly selective PI3K inhibitor, is currently being investigated in phase I/II clinical trials. The mechanisms of action of NVP-BKM120 in colon cancer cells are unclear. In the present study, we investigated how NVP-BKM120 suppresses colon cancer cells growth and potentiates...

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Autores principales: Yang, Shida, Li, Xin, Guan, Wenchang, Qian, Mingqin, Yao, Zhicheng, Yin, Xiaoxue, Zhao, Hongmei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Research Paper
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669949/
https://www.ncbi.nlm.nih.gov/pubmed/29137323
http://dx.doi.org/10.18632/oncotarget.20943
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author Yang, Shida
Li, Xin
Guan, Wenchang
Qian, Mingqin
Yao, Zhicheng
Yin, Xiaoxue
Zhao, Hongmei
author_facet Yang, Shida
Li, Xin
Guan, Wenchang
Qian, Mingqin
Yao, Zhicheng
Yin, Xiaoxue
Zhao, Hongmei
author_sort Yang, Shida
collection PubMed
description NVP-BKM120, a potent and highly selective PI3K inhibitor, is currently being investigated in phase I/II clinical trials. The mechanisms of action of NVP-BKM120 in colon cancer cells are unclear. In the present study, we investigated how NVP-BKM120 suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. We found that NVP-BKM120 treatment enhance PUMA induction irrespective of p53 status through the FoxO3a pathway following AKT inhibition. Furthermore, PUMA is required for NVP-BKM120-induced apoptosis in colon cancer cells. In addition, NVP-BKM120 also synergized with 5-Fluorouracil or regorafenib to induce marked apoptosis via PUMA induction. Deficiency of PUMA suppressed apoptosis and antitumor effect of NVP-BKM120 in xenograft model. These results demonstrate a key role of PUMA in mediating the anticancer effects of NVP-BKM120 and suggest that PUMA could be used as an indicator of NVP-BKM120 sensitivity, and also have important implications for it clinical applications.
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spelling pubmed-56699492017-11-09 NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction Yang, Shida Li, Xin Guan, Wenchang Qian, Mingqin Yao, Zhicheng Yin, Xiaoxue Zhao, Hongmei Oncotarget Research Paper NVP-BKM120, a potent and highly selective PI3K inhibitor, is currently being investigated in phase I/II clinical trials. The mechanisms of action of NVP-BKM120 in colon cancer cells are unclear. In the present study, we investigated how NVP-BKM120 suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. We found that NVP-BKM120 treatment enhance PUMA induction irrespective of p53 status through the FoxO3a pathway following AKT inhibition. Furthermore, PUMA is required for NVP-BKM120-induced apoptosis in colon cancer cells. In addition, NVP-BKM120 also synergized with 5-Fluorouracil or regorafenib to induce marked apoptosis via PUMA induction. Deficiency of PUMA suppressed apoptosis and antitumor effect of NVP-BKM120 in xenograft model. These results demonstrate a key role of PUMA in mediating the anticancer effects of NVP-BKM120 and suggest that PUMA could be used as an indicator of NVP-BKM120 sensitivity, and also have important implications for it clinical applications. Impact Journals LLC 2017-09-15 /pmc/articles/PMC5669949/ /pubmed/29137323 http://dx.doi.org/10.18632/oncotarget.20943 Text en Copyright: © 2017 Yang et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Yang, Shida
Li, Xin
Guan, Wenchang
Qian, Mingqin
Yao, Zhicheng
Yin, Xiaoxue
Zhao, Hongmei
NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction
title NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction
title_full NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction
title_fullStr NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction
title_full_unstemmed NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction
title_short NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction
title_sort nvp-bkm120 inhibits colon cancer growth via foxo3a-dependent puma induction
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669949/
https://www.ncbi.nlm.nih.gov/pubmed/29137323
http://dx.doi.org/10.18632/oncotarget.20943
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