Identification of phosphoenolpyruvate carboxykinase 1 as a potential therapeutic target for pancreatic cancer

Xiao-Ren Zhu,Xiao-Yu Chen,Chun-Xia Feng,Shi-Qing Peng,Min-Bin Chen,Yuan-Yuan Liu,Le Wang

doi:10.1038/s41419-021-04201-w

Abstract

Pancreatic cancer is the third leading cause of cancer-related mortalities and is characterized by rapid disease progression. Identification of novel therapeutic targets for this devastating disease is important. Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme of gluconeogenesis. The current study tested the expression and potential functions of PCK1 in pancreatic cancer. We show that PCK1 mRNA and protein levels are significantly elevated in human pancreatic cancer tissues and cells. In established and primary pancreatic cancer cells, PCK1 silencing (by shRNA) or CRISPR/Cas9-induced PCK1 knockout potently inhibited cell growth, proliferation, migration and invasion, and induced robust apoptosis activation. Conversely, ectopic overexpression of PCK1 in pancreatic cancer cells accelerated cell proliferation and migration. RNA-seq analyzing of differentially expressed genes (DEGs) in PCK1-silenced pancreatic cancer cells implied that DEGs were enriched in the PI3K-Akt-mTOR cascade. In pancreatic cancer cells, Akt-mTOR activation was largely inhibited by PCK1 shRNA, but was augmented after ectopic PCK1 overexpression. In vivo, the growth of PCK1 shRNA-bearing PANC-1 xenografts was largely inhibited in nude mice. Akt-mTOR activation was suppressed in PCK1 shRNA-expressing PANC-1 xenograft tissues. Collectively, PCK1 is a potential therapeutic target for pancreatic cancer.

Highlights

Abnormal activation of multiple signaling cascades are closely associated with the initiation and progression of pancreatic cancer [1]
Phosphoenolpyruvate carboxykinase 1 (PCK1) is overexpressed in human pancreatic cancer tissues and cells First The Cancer Genome Atlas (TCGA) cohort was consulted to examine PCK1 expression in pancreatic ductal adenocarcinoma (PDAC)
The GTEx project analyzing the RNA-Seq data of human cancers demonstrated that PCK1 mRNA levels in pancreatic cancer tissues (“T”) were significantly higher than those in normal pancreatic tissues (“N”) (Fig. 1B)

Summary

Introduction

Abnormal activation of multiple signaling cascades are closely associated with the initiation and progression of pancreatic cancer [1]. Multiple inhibitors/antibodies targeting EGFR, VEGFR, PDGFR, cyclindependent kinases, and Src kinases are in various phases of clinical trials testing their efficacy against pancreatic cancer [4,5,6]. It is important to identify novel kinases that are vital for pancreatic cancer progression. Phosphoenolpyruvate carboxykinase (PCK) is the first ratelimiting enzyme of gluconeogenesis that converts oxaloacetate and GTP into phosphoenolpyruvate (PEP) and CO2 [7]. It plays a vital role in gluconeogenesis [8]. Activated PCK1 can translocate into the endoplasmic reticulum [10]

Methods

Results

Conclusion