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

Fei Shao,Fei Shao,Fei Shao,Hongfei Jiang,Xueli Bian,Hongfei Jiang,Dongming Xing,Lei Zhu,Daqian Xu,Juhong Wang,Wei Guo,Shuai Wang,Gaoxiang Zhao,Shuai Wang,Lei Zhu,Zhimin Lu,Dongming Xing,Yibo Gao,Xueli Bian,Jie He,Dongming Xing

doi:10.3389/fonc.2021.561247

Abstract

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.

Highlights

Lung cancer is a leading cause of cancer-related death worldwide [1]
We treated human nonsmall-cell lung carcinoma (NSCLC) cells with epidermal growth factor (EGF) and found that epidermal growth factor receptor (EGFR) activation induced a substantial increase of phosphorylation levels of AKT S473, Phosphoenolpyruvate carboxykinase 1 (PCK1) S90, INSIG1 S207 and INSIG2 S151, and the cleavage of sterol regulatory element-binding protein 1 (SREBP1) in H1395 lung adenocarcinoma (LUAD) cells and H226 lung squamous cell carcinoma (LUSC) cells
We examined a panel of NSCLC cell lines, including A549, H358, H460, H1299, H1395, H1993, H322M, and H226, and showed that PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 accumulation were correlated with each other (Figure 1B)

Summary

Introduction

Lung cancer is a leading cause of cancer-related death worldwide [1]. Non-small-cell lung carcinoma (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all cases [2]. Blockade of AKT-mediated phosphorylation of PCK1 and PCK1-mediated phosphorylation of INSIG1/2 inhibits lipid synthesis, hepatocellular carcinoma (HCC) cell proliferation, and tumor formation in mice [8, 9]. These findings underscore the significance of the newly identified protein kinase activity of gluconeogenesis enzyme PCK1 in nuclear SREBP1 activation, lipogenesis, and HCC development [8]. The role of PCK1-dependent lipogenesis in HCC cell proliferation was revealed, whether AKT-phosphorylated PCK1 pS90, INSIG1 pS207/INSIG2 pS151, or nuclear SREBP1 expression is associated with progression and prognosis in NSCLC patients is unknown

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Conclusion