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Prognostic Impact of PCK1 Protein Kinase Activity-Dependent Nuclear SREBP1 Activation in Non-Small-Cell Lung Carcinoma

Metabolic enzymes can perform non-metabolic functions and play critical roles in the regulation of a variety of important cellular activities. Phosphoenolpyruvate carboxykinase 1 (PCK1), a gluconeogenesis enzyme, was recently identified as an AKT-regulated protein kinase that phosphorylates INSIG1/2...

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Autores principales: Shao, Fei, Bian, Xueli, Wang, Juhong, Xu, Daqian, Guo, Wei, Jiang, Hongfei, Zhao, Gaoxiang, Zhu, Lei, Wang, Shuai, Xing, Dongming, Gao, Yibo, He, Jie, Lu, Zhimin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033018/
https://www.ncbi.nlm.nih.gov/pubmed/33842305
http://dx.doi.org/10.3389/fonc.2021.561247
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author Shao, Fei
Bian, Xueli
Wang, Juhong
Xu, Daqian
Guo, Wei
Jiang, Hongfei
Zhao, Gaoxiang
Zhu, Lei
Wang, Shuai
Xing, Dongming
Gao, Yibo
He, Jie
Lu, Zhimin
author_facet Shao, Fei
Bian, Xueli
Wang, Juhong
Xu, Daqian
Guo, Wei
Jiang, Hongfei
Zhao, Gaoxiang
Zhu, Lei
Wang, Shuai
Xing, Dongming
Gao, Yibo
He, Jie
Lu, Zhimin
author_sort Shao, Fei
collection PubMed
description Metabolic enzymes can perform non-metabolic functions and play critical roles in the regulation of a variety of important cellular activities. Phosphoenolpyruvate carboxykinase 1 (PCK1), a gluconeogenesis enzyme, was recently identified as an AKT-regulated protein kinase that phosphorylates INSIG1/2 to promote nuclear SREBP1-dependent lipogenesis. However, the relationship of this regulation with the progression of non-small-cell lung carcinoma (NSCLC) is unclear. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces AKT-dependent PCK1 pS90, PCK1-mediated INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 accumulation in NSCLC cells. In addition, the expression levels of AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 are higher in 451 analyzed human NSCLC specimens than in their adjacent normal tissues and positively correlated with each other in the tumor specimens. Furthermore, the expression levels of PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 are associated with TNM stage and progression in NSCLC. Importantly, levels of PCK1 pS90 or INSIG1 pS207/INSIG2 pS151 are positively correlated with poor prognosis in NSCLC patients, and the combined expression value of the PCK1 and INSIG1/2 phosphorylation has a better prognostic value than that of each individual protein phosphorylation value and is an independent prognostic marker for NSCLC. These findings reveal the role of PCK1-mediated nuclear SREBP1 activation in NSCLC progression and highlight the potential to target the protein kinase activity of PCK1 for the diagnosis and treatment of human NSCLC.
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spelling pubmed-80330182021-04-10 Prognostic Impact of PCK1 Protein Kinase Activity-Dependent Nuclear SREBP1 Activation in Non-Small-Cell Lung Carcinoma Shao, Fei Bian, Xueli Wang, Juhong Xu, Daqian Guo, Wei Jiang, Hongfei Zhao, Gaoxiang Zhu, Lei Wang, Shuai Xing, Dongming Gao, Yibo He, Jie Lu, Zhimin Front Oncol Oncology Metabolic enzymes can perform non-metabolic functions and play critical roles in the regulation of a variety of important cellular activities. Phosphoenolpyruvate carboxykinase 1 (PCK1), a gluconeogenesis enzyme, was recently identified as an AKT-regulated protein kinase that phosphorylates INSIG1/2 to promote nuclear SREBP1-dependent lipogenesis. However, the relationship of this regulation with the progression of non-small-cell lung carcinoma (NSCLC) is unclear. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces AKT-dependent PCK1 pS90, PCK1-mediated INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 accumulation in NSCLC cells. In addition, the expression levels of AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 are higher in 451 analyzed human NSCLC specimens than in their adjacent normal tissues and positively correlated with each other in the tumor specimens. Furthermore, the expression levels of PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 are associated with TNM stage and progression in NSCLC. Importantly, levels of PCK1 pS90 or INSIG1 pS207/INSIG2 pS151 are positively correlated with poor prognosis in NSCLC patients, and the combined expression value of the PCK1 and INSIG1/2 phosphorylation has a better prognostic value than that of each individual protein phosphorylation value and is an independent prognostic marker for NSCLC. These findings reveal the role of PCK1-mediated nuclear SREBP1 activation in NSCLC progression and highlight the potential to target the protein kinase activity of PCK1 for the diagnosis and treatment of human NSCLC. Frontiers Media S.A. 2021-03-26 /pmc/articles/PMC8033018/ /pubmed/33842305 http://dx.doi.org/10.3389/fonc.2021.561247 Text en Copyright © 2021 Shao, Bian, Wang, Xu, Guo, Jiang, Zhao, Zhu, Wang, Xing, Gao, He and Lu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Shao, Fei
Bian, Xueli
Wang, Juhong
Xu, Daqian
Guo, Wei
Jiang, Hongfei
Zhao, Gaoxiang
Zhu, Lei
Wang, Shuai
Xing, Dongming
Gao, Yibo
He, Jie
Lu, Zhimin
Prognostic Impact of PCK1 Protein Kinase Activity-Dependent Nuclear SREBP1 Activation in Non-Small-Cell Lung Carcinoma
title Prognostic Impact of PCK1 Protein Kinase Activity-Dependent Nuclear SREBP1 Activation in Non-Small-Cell Lung Carcinoma
title_full Prognostic Impact of PCK1 Protein Kinase Activity-Dependent Nuclear SREBP1 Activation in Non-Small-Cell Lung Carcinoma
title_fullStr Prognostic Impact of PCK1 Protein Kinase Activity-Dependent Nuclear SREBP1 Activation in Non-Small-Cell Lung Carcinoma
title_full_unstemmed Prognostic Impact of PCK1 Protein Kinase Activity-Dependent Nuclear SREBP1 Activation in Non-Small-Cell Lung Carcinoma
title_short Prognostic Impact of PCK1 Protein Kinase Activity-Dependent Nuclear SREBP1 Activation in Non-Small-Cell Lung Carcinoma
title_sort prognostic impact of pck1 protein kinase activity-dependent nuclear srebp1 activation in non-small-cell lung carcinoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033018/
https://www.ncbi.nlm.nih.gov/pubmed/33842305
http://dx.doi.org/10.3389/fonc.2021.561247
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