Elevated nuclear localization of glycolytic enzyme TPI1 promotes lung adenocarcinoma and enhances chemoresistance

Peng Liu,Yue Xiong,Lei Zhang,Yun Gao,Si-Jia Sun,Ying-Jie Ai,Xu Feng,Hai-Xin Yuan,Jin-Ye Zhang,Miao Lin,Yi-Ping Sun,Yi-Min Zheng

doi:10.1038/s41419-022-04655-6

Abstract

Increased glycolysis is a hallmark of tumor, which can provide tumor cells with energy and building blocks to promote cell proliferation. Recent studies have shown that not only the expression of glycolytic genes but also their subcellular localization undergoes a variety of changes to promote development of different types of tumors. In this study, we performed a comprehensive analysis of glycolysis and gluconeogenesis genes based on data from TCGA to identify those with significant tumor-promoting potential across 14 types of tumors. This analysis not only confirms genes that are known to be involved in tumorigenesis, but also reveals a significant correlation of triosephosphate isomerase 1 (TPI1) with poor prognosis, especially in lung adenocarcinoma (LUAD). TPI1 is a glycolytic enzyme that interconverts dihydroxyacetone phosphate (DHAP) to glyceraldehyde 3-phosphate (GAP). We confirm the upregulation of TPI1 expression in clinical LUAD samples and an inverse correlation with the overall patient survival. Knocking down of TPI1 in lung cancer cells significantly reduced cell migration, colony formation, and xenograft tumor growth. Surprisingly, we found that the oncogenic function of TPI1 depends on its translocation to cell nucleus rather than its catalytic activity. Significant accumulation of TPI1 in cell nucleus was observed in LUAD tumor tissues compared with the cytoplasm localization in adjacent normal tissues. Moreover, nuclear translocation of TPI1 is induced by extracellular stress (such as chemotherapy agents and peroxide), which facilitates the chemoresistance of cancer cells. Our study uncovers a novel function of the glycolytic enzyme TPI1 in the LUAD.

Highlights

Lung cancer is one of the most common tumors and the leading cause of cancer-related death in the world, with 2.1 million people diagnosed and 1.76 million deaths annually [1]
triosephosphate isomerase 1 (TPI1) is upregulated in lung adenocarcinoma To identify the key metabolic enzymes in glycolysis and gluconeogenesis pathway that are important for tumorigenesis, we performed a comprehensive expression analysis of these genes across 14 types of tumors with TCGA database
GPI1, TPI1, GAPDH, PGK1, and pyruvate kinase M2 (PKM2) were consistently upregulated in almost all tumor types, while PCK1, PCK2, and FBP1 were downregulated in tumors (Fig. 1A)

Summary

Introduction

Lung cancer is one of the most common tumors and the leading cause of cancer-related death in the world, with 2.1 million people diagnosed and 1.76 million deaths annually [1]. Small cell lung cancer (SCLC) and non-SCLC (NSCLC) are the main types of lung cancer, accounting for 15% and 85%, respectively [2]. Lung adenocarcinoma (LUAD) is the most prevalent subtype of NSCLC, accounting for approximately 50% of all lung cancer cases [1]. Instead of empiric use of cytotoxic therapies, patients are tested for oncogenic drivers and receive effective and better-tolerated regimens that are targeted to specific molecular subtypes in LUAD [5–8]. Epidermal growth factor receptor (EGFR) mutationpositive patients benefit greatly from EGFR tyrosine kinase inhibitors (EGFR TKIs), having a response rate as high as 80%, and around 10–14 months of progression-free survival (PFS) [9]. Most patients develop drug resistance within about 1 year of EGFR TKIs treatment [10]. Identification of new molecular targets has high significance for new LUAD therapy

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Results

Conclusion