Akt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells

Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancy-related deaths. p53 mutation in HCC associates with worse clinicopathologic features including therapeutic limitation. A combination of targeted therapy may have some advantages. Akt/mTOR signaling contributes to the regula...

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Autores principales:	Tapas Patra, Keith Meyer, Ratna B. Ray, Tatsuo Kanda, Ranjit Ray
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/3e23d0b8a3bc45bab032fe4d6ec552a6
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spelling	oai:doaj.org-article:3e23d0b8a3bc45bab032fe4d6ec552a62021-11-14T12:06:55ZAkt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells10.1038/s41419-021-04371-72041-4889https://doaj.org/article/3e23d0b8a3bc45bab032fe4d6ec552a62021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04371-7https://doaj.org/toc/2041-4889Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancy-related deaths. p53 mutation in HCC associates with worse clinicopathologic features including therapeutic limitation. A combination of targeted therapy may have some advantages. Akt/mTOR signaling contributes to the regulation of cell proliferation and cell death. Akt inhibitor (AZD5363) and mTORC1/2 dual inhibitor (AZD8055) are in a clinical trial for HCC and other cancers. In this study, we examined whether these inhibitors successfully induce antiproliferative activity in p53 mutant HCC cells, and the underlying mechanisms. We observed that a combination of AZD5363 and AZD8055 treatment synergizes antiproliferative activity on p53 mutated or wild-type HCC cell lines and induces apoptotic cell death. Mechanistic insights indicate that a combination of AZD5363 and AZD8055 activated FOXO3a to induce Bim-associated apoptosis in p53 mutated HCC cells, whereas cells retaining functional p53 enhanced Bax. siRNA-mediated knock-down of Bim or Bax prevented apoptosis in inhibitor-treated cells. We further observed a combination of treatment inhibits phosphorylation of FOXO3a and protects FOXO3a from MDM2 mediated degradation by preventing the phosphorylation of Akt and SGK1. FOXO3a accumulates in the nucleus under these conditions and induces Bim transcription in p53 mutant HCC cells. Combination treatment in the HCC cells expressing wild-type p53 causes interference of FOXO3a function for direct interaction with functional p53 and unable to induce Bim-associated cell death. On the other hand, Bim-associated cell death occurs in p53 mutant cells due to uninterrupted FOXO3a function. Overall, our findings suggested that a combined regimen of dual mTORC1/2 and Akt inhibitors may be an effective therapeutic strategy for HCC patients harboring p53 mutation.Tapas PatraKeith MeyerRatna B. RayTatsuo KandaRanjit RayNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 11, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Tapas Patra Keith Meyer Ratna B. Ray Tatsuo Kanda Ranjit Ray Akt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells
description	Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancy-related deaths. p53 mutation in HCC associates with worse clinicopathologic features including therapeutic limitation. A combination of targeted therapy may have some advantages. Akt/mTOR signaling contributes to the regulation of cell proliferation and cell death. Akt inhibitor (AZD5363) and mTORC1/2 dual inhibitor (AZD8055) are in a clinical trial for HCC and other cancers. In this study, we examined whether these inhibitors successfully induce antiproliferative activity in p53 mutant HCC cells, and the underlying mechanisms. We observed that a combination of AZD5363 and AZD8055 treatment synergizes antiproliferative activity on p53 mutated or wild-type HCC cell lines and induces apoptotic cell death. Mechanistic insights indicate that a combination of AZD5363 and AZD8055 activated FOXO3a to induce Bim-associated apoptosis in p53 mutated HCC cells, whereas cells retaining functional p53 enhanced Bax. siRNA-mediated knock-down of Bim or Bax prevented apoptosis in inhibitor-treated cells. We further observed a combination of treatment inhibits phosphorylation of FOXO3a and protects FOXO3a from MDM2 mediated degradation by preventing the phosphorylation of Akt and SGK1. FOXO3a accumulates in the nucleus under these conditions and induces Bim transcription in p53 mutant HCC cells. Combination treatment in the HCC cells expressing wild-type p53 causes interference of FOXO3a function for direct interaction with functional p53 and unable to induce Bim-associated cell death. On the other hand, Bim-associated cell death occurs in p53 mutant cells due to uninterrupted FOXO3a function. Overall, our findings suggested that a combined regimen of dual mTORC1/2 and Akt inhibitors may be an effective therapeutic strategy for HCC patients harboring p53 mutation.
format	article
author	Tapas Patra Keith Meyer Ratna B. Ray Tatsuo Kanda Ranjit Ray
author_facet	Tapas Patra Keith Meyer Ratna B. Ray Tatsuo Kanda Ranjit Ray
author_sort	Tapas Patra
title	Akt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells
title_short	Akt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells
title_full	Akt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells
title_fullStr	Akt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells
title_full_unstemmed	Akt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells
title_sort	akt inhibitor augments anti-proliferative efficacy of a dual mtorc1/2 inhibitor by foxo3a activation in p53 mutated hepatocarcinoma cells
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/3e23d0b8a3bc45bab032fe4d6ec552a6
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Akt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells

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