Bifunctional enzyme ATIC promotes propagation of hepatocellular carcinoma by regulating AMPK-mTOR-S6\xa0K1 signaling

Minjing Li,Ling Zhou,Yancun Yin,Defang Li,Maolei Xu,Changzhu Jin

doi:10.1186/s12964-017-0208-8

Minjing Li, Ling Zhou + Show 4 more

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https://doi.org/10.1186/s12964-017-0208-8

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Abstract

BackgroundHepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. To effectively treat HCC, new molecular targets and therapeutic approaches must be identified. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), a bifunctional protein enzyme, catalyzes the last two steps of the de novo purine biosynthetic pathway. Whether ATIC contributes to cancer development remains unclear.MethodsATIC mRNA levels in different types of human HCC samples or normal tissues were determined from Gene Expression across Normal and Tumor tissue (GENT) database. The expression level of ATIC in human HCC samples or cell lines were examined by RT-PCR and western blot. Overall survival and disease-free survival of HCC patients in the ATIC low and ATIC high groups were determined by Kaplan-Meier analysis. Effects of ATIC knockdown by lentivirus infection were evaluated on cell-proliferation, cell-apoptosis, colony formation and migration. The mechanisms involved in HCC cells growth, apoptosis and migration were analyzed by western blot and Compound C (C-C) rescue assays.ResultsHere, we first demonstrated that expression of ATIC is aberrantly up-regulated in HCC tissues and high level of ATIC is correlated with poor survival in HCC patients. Knockdown of ATIC expression resulted in a dramatic decrease in proliferation, colony formation and migration of HCC cells. We also identified ATIC as a novel regulator of adenosine monophosphate-activated protein kinase (AMPK) and its downstream signaling mammalian target of rapamycin (mTOR). ATIC suppresses AMPK activation, thus activates mTOR-S6 K1-S6 signaling and supports growth and motility activity of HCC cells.ConclusionTaken together, our results indicate that ATIC acts as an oncogenic gene that promotes survival, proliferation and migration by targeting AMPK-mTOR-S6 K1 signaling.

Highlights

Hepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis
Consistent with these results, Gene Expression across Normal and Tumor tissue (GENT) analysis results showed that ATIC expression was significantly upregulated in HCC samples compared to normal tissues (Fig. 1d)
We further examined the expression of ATIC in several HCC cell lines, including Huh-7, SMMC7721, Hep3B and HepG2

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. To effectively treat HCC, new molecular targets and therapeutic approaches must be identified. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), a bifunctional protein enzyme, catalyzes the last two steps of the de novo purine biosynthetic pathway. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), a bifunctional protein enzyme, catalyzes the last two steps of the de novo purine biosynthetic pathway. Hepatocellular Carcinoma (HCC), one of the most common and lethal cancers, is the second leading cause of cancer death worldwide [1]. To satisfy the metabolic requirements associated with a high growth rate, cancer cells often increase the use of anabolic pathways. Cancer cells maintain de novo purine synthesis pathway at high levels that support anabolic growth [4, 5]. The de novo purine synthesis pathway contains 10 sequential steps, beginning with phosphoribosyl pyrophosphate and ending with IMP. Purine synthesis pathway is strongly correlated with rates of proliferation of cancer cells [7, 8]. Whether and how ATIC modulates progression of cancer remains largely unknown

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