Knockdown of PAICS inhibits malignant proliferation of human breast cancer cell lines

Minjun Meng,Jianbo Jia,Lianghui Li,Yanling Chen,Sumei Yang

doi:10.1186/s40659-018-0172-9

Abstract

BackgroundPhosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an enzyme required for de novo purine biosynthesis, is associated with and involved in tumorigenesis. This study aimed to evaluate the role of PAICS in human breast cancer, which remains the most frequently diagnosed cancer and the leading cause of cancer-related death among women in less developed countries.ResultsLentivirus-based short hairpin RNA targeting PAICS specifically depleted its endogenous expression in ZR-75-30 and MDA-MB-231 breast cancer cells. Depletion of PAICS led to a significant decrease in cell viability and proliferation. To ascertain the mechanisms through which PAICS modulates cell proliferation, flow cytometry was performed, and it was confirmed that G1-S transition was blocked in ZR-75-30 cells through PAICS knockdown. This might have occurred partly through the suppression of Cyclin E and the upregulation of Cyclin D1, P21, and CDK4. Moreover, PAICS knockdown obviously promoted cell apoptosis in ZR-75-30 cells through the activation of PARP and caspase 3 and downregulation of Bcl-2 and Bcl-xl expression in ZR-75-30 cells.ConclusionsThese findings demonstrate that PAICS plays an essential role in breast cancer proliferation in vitro, which provides a new opportunity for discovering and identifying novel effective treatment strategies.

Highlights

Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an enzyme required for de novo purine biosynthesis, is associated with and involved in tumorigenesis
Knockdown of PAICS expression with lentivirus‐delivered short hairpin RNA (shRNA) ZR-75-30 and MDA-MB-231 cells were transduced with shRNA-expressing lentivirus
The inhibitory effect of PAICS shRNA on its endogenous expression in ZR-75-30 and MDA-MB-231 cells was separately examined by qRTPCR and western blotting

Summary

Introduction

Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an enzyme required for de novo purine biosynthesis, is associated with and involved in tumorigenesis. The phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) gene encodes a bifunctional enzyme that has phosphoribosylaminoimidazole carboxylase activity in its N-terminal region and phosphoribosylaminoimidazole succinocarboxamide synthetase activity in its C-terminal region [3]. This enzyme catalyzes steps 6 and 7 of the de novo purine biosynthesis pathway (Phosphoribosyl pyrophosphate amidotransferase (PPAT) catalyses step 1; phosphoribosylglycinamide formyltransferase (GART) steps 2, 3 and 5; phosphoribosylformylglycinamidine synthase (PFAS) step 4; phosphoribosylaminoimidazole carboxylase (PAICS) steps 6 and 7; adenylosuccinate lyase (ADSL) step 8 and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) steps 9 and 10) [4]. Through a functional yeast survival screen of tumor-derived cDNA libraries, PAICS was shown to be overexpressed in certain tumor

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