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Inhibition of AKT induces p53/SIRT6/PARP1-dependent parthanatos to suppress tumor growth

BACKGROUND: Targeting AKT suppresses tumor growth through inducing apoptosis, however, during which whether other forms of cell death occurring is poorly understood. METHODS: The effects of increasing PARP1 dependent cell death (parthanatos) induced by inhibiting AKT on cell proliferation were deter...

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Autores principales: Zhang, Yizheng, Zhang, Chuchu, Li, Jiehan, Jiang, Meimei, Guo, Shuning, Yang, Ge, Zhang, Lingling, Wang, Feng, Yi, Shiqi, Wang, Jiangang, Fu, Yang, Zhang, Yingjie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205131/
https://www.ncbi.nlm.nih.gov/pubmed/35715817
http://dx.doi.org/10.1186/s12964-022-00897-1
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author Zhang, Yizheng
Zhang, Chuchu
Li, Jiehan
Jiang, Meimei
Guo, Shuning
Yang, Ge
Zhang, Lingling
Wang, Feng
Yi, Shiqi
Wang, Jiangang
Fu, Yang
Zhang, Yingjie
author_facet Zhang, Yizheng
Zhang, Chuchu
Li, Jiehan
Jiang, Meimei
Guo, Shuning
Yang, Ge
Zhang, Lingling
Wang, Feng
Yi, Shiqi
Wang, Jiangang
Fu, Yang
Zhang, Yingjie
author_sort Zhang, Yizheng
collection PubMed
description BACKGROUND: Targeting AKT suppresses tumor growth through inducing apoptosis, however, during which whether other forms of cell death occurring is poorly understood. METHODS: The effects of increasing PARP1 dependent cell death (parthanatos) induced by inhibiting AKT on cell proliferation were determined by CCK-8 assay, colony formation assay, Hoechst 33,258 staining and analysis of apoptotic cells by flow cytometry. For the detailed mechanisms during this process, Western blot analysis, qRT-PCR analysis, immunofluorescence and co-immunoprecipitation were performed. Moreover, the inhibition of tumor growth by inducing p53/SIRT6/PARP1-dependent parthanatos was further verified in the xenograft mouse model. RESULTS: For the first time, we identified that inhibiting AKT triggered parthanatos, a new form of regulated cell death, leading to colon cancer growth suppression. For the mechanism investigation, we found that after pharmacological or genetic AKT inhibition, p53 interacted with SIRT6 and PARP1 directly to activate it, and promoted the formation of PAR polymer. Subsequently, PAR polymer transported to outer membrane of mitochondria and resulted in AIF releasing and translocating to nucleus thus promoting cell death. While, blocking PARP1 activity significantly rescued colon cancer from death. Furthermore, p53 deletion or mutation eliminated PAR polymer formation, AIF translocation, and PARP1 dependent cell death, which was promoted by overexpression of SIRT6. Meanwhile, reactive oxygen species production was elevated after inhibition of AKT, which might also play a role in the occurrence of parthanatos. In addition, inhibiting AKT initiated protective autophagy simultaneously, which advanced tumor survival and growth. CONCLUSION: Our findings demonstrated that AKT inhibition induced p53-SIRT6-PARP1 complex formation and the activation of parthanatos, which can be recognized as a novel potential therapeutic strategy for cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-022-00897-1.
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spelling pubmed-92051312022-06-18 Inhibition of AKT induces p53/SIRT6/PARP1-dependent parthanatos to suppress tumor growth Zhang, Yizheng Zhang, Chuchu Li, Jiehan Jiang, Meimei Guo, Shuning Yang, Ge Zhang, Lingling Wang, Feng Yi, Shiqi Wang, Jiangang Fu, Yang Zhang, Yingjie Cell Commun Signal Research BACKGROUND: Targeting AKT suppresses tumor growth through inducing apoptosis, however, during which whether other forms of cell death occurring is poorly understood. METHODS: The effects of increasing PARP1 dependent cell death (parthanatos) induced by inhibiting AKT on cell proliferation were determined by CCK-8 assay, colony formation assay, Hoechst 33,258 staining and analysis of apoptotic cells by flow cytometry. For the detailed mechanisms during this process, Western blot analysis, qRT-PCR analysis, immunofluorescence and co-immunoprecipitation were performed. Moreover, the inhibition of tumor growth by inducing p53/SIRT6/PARP1-dependent parthanatos was further verified in the xenograft mouse model. RESULTS: For the first time, we identified that inhibiting AKT triggered parthanatos, a new form of regulated cell death, leading to colon cancer growth suppression. For the mechanism investigation, we found that after pharmacological or genetic AKT inhibition, p53 interacted with SIRT6 and PARP1 directly to activate it, and promoted the formation of PAR polymer. Subsequently, PAR polymer transported to outer membrane of mitochondria and resulted in AIF releasing and translocating to nucleus thus promoting cell death. While, blocking PARP1 activity significantly rescued colon cancer from death. Furthermore, p53 deletion or mutation eliminated PAR polymer formation, AIF translocation, and PARP1 dependent cell death, which was promoted by overexpression of SIRT6. Meanwhile, reactive oxygen species production was elevated after inhibition of AKT, which might also play a role in the occurrence of parthanatos. In addition, inhibiting AKT initiated protective autophagy simultaneously, which advanced tumor survival and growth. CONCLUSION: Our findings demonstrated that AKT inhibition induced p53-SIRT6-PARP1 complex formation and the activation of parthanatos, which can be recognized as a novel potential therapeutic strategy for cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-022-00897-1. BioMed Central 2022-06-17 /pmc/articles/PMC9205131/ /pubmed/35715817 http://dx.doi.org/10.1186/s12964-022-00897-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Zhang, Yizheng
Zhang, Chuchu
Li, Jiehan
Jiang, Meimei
Guo, Shuning
Yang, Ge
Zhang, Lingling
Wang, Feng
Yi, Shiqi
Wang, Jiangang
Fu, Yang
Zhang, Yingjie
Inhibition of AKT induces p53/SIRT6/PARP1-dependent parthanatos to suppress tumor growth
title Inhibition of AKT induces p53/SIRT6/PARP1-dependent parthanatos to suppress tumor growth
title_full Inhibition of AKT induces p53/SIRT6/PARP1-dependent parthanatos to suppress tumor growth
title_fullStr Inhibition of AKT induces p53/SIRT6/PARP1-dependent parthanatos to suppress tumor growth
title_full_unstemmed Inhibition of AKT induces p53/SIRT6/PARP1-dependent parthanatos to suppress tumor growth
title_short Inhibition of AKT induces p53/SIRT6/PARP1-dependent parthanatos to suppress tumor growth
title_sort inhibition of akt induces p53/sirt6/parp1-dependent parthanatos to suppress tumor growth
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205131/
https://www.ncbi.nlm.nih.gov/pubmed/35715817
http://dx.doi.org/10.1186/s12964-022-00897-1
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