De novo deoxyribonucleotide biosynthesis regulates cell growth and tumor progression in small-cell lung carcinoma

Ami Maruyama,Joji Nakayama,Tomoyoshi Soga,Yuzo Sato,Junko Murai,Hideki Makinoshima,Takamasa Ishikawa

doi:10.1038/s41598-021-92948-9

Abstract

Deoxyribonucleotide biosynthesis from ribonucleotides supports the growth of active cancer cells by producing building blocks for DNA. Although ribonucleotide reductase (RNR) is known to catalyze the rate-limiting step of de novo deoxyribonucleotide triphosphate (dNTP) synthesis, the biological function of the RNR large subunit (RRM1) in small-cell lung carcinoma (SCLC) remains unclear. In this study, we established siRNA-transfected SCLC cell lines to investigate the anticancer effect of silencing RRM1 gene expression. We found that RRM1 is required for the full growth of SCLC cells both in vitro and in vivo. In particular, the deletion of RRM1 induced a DNA damage response in SCLC cells and decreased the number of cells with S phase cell cycle arrest. We also elucidated the overall changes in the metabolic profile of SCLC cells caused by RRM1 deletion. Together, our findings reveal a relationship between the deoxyribonucleotide biosynthesis axis and key metabolic changes in SCLC, which may indicate a possible link between tumor growth and the regulation of deoxyribonucleotide metabolism in SCLC.

Highlights

Deoxyribonucleotide biosynthesis from ribonucleotides supports the growth of active cancer cells by producing building blocks for DNA
We measured the expression of ribonucleotide reductase (RNR)-related proteins (RRM1, RRM2, and RRM2B) in small-cell lung carcinoma (SCLC) cell lines using western blotting (Fig. S3)
SCLC is associated with a poor prognosis due to metastatic dissemination, drug resistance, and a lack of therapeutic targets; recent studies have demonstrated that SCLC displays characteristic abnormalities in nucleic acid metabolism

Summary

Introduction

Deoxyribonucleotide biosynthesis from ribonucleotides supports the growth of active cancer cells by producing building blocks for DNA. Ribonucleotide reductase (RNR) is known to catalyze the rate-limiting step of de novo deoxyribonucleotide triphosphate (dNTP) synthesis, the biological function of the RNR large subunit (RRM1) in small-cell lung carcinoma (SCLC) remains unclear. De novo dNTP synthesis is associated with the cell cycle and supplies the most deoxynucleotides during S phase for the replication of genomic DNA17,18. The de novo biosynthesis of deoxycytidine triphosphate (dCTP), deoxyadenosine triphosphate (dATP), and deoxyguanosine triphosphate (dGTP) is highly dependent on the activity of ribonucleotide reductase (RNR, Fig. S1), which catalyzes the rate-limiting step in dNTP synthesis and is a well-recognized target for cancer therapy[20,21]. Several RNR protein regulatory mechanisms have been reported involving post-translational m odification[31,32]; little is known about the biological role of RRM1 in SCLC

Methods

Results

Conclusion