Data from Metabolic Hallmarks for Purine Nucleotide Biosynthesis in Small Cell Lung Carcinoma

Abstract

<div>Abstract<p>Small cell lung cancer (SCLC) has a poor prognosis, emphasizing the necessity for developing new therapies. The <i>de novo</i> synthesis pathway of purine nucleotides, which is involved in the malignant growth of SCLC, has emerged as a novel therapeutic target. Purine nucleotides are supplied by two pathways: <i>de novo</i> and salvage. However, the role of the salvage pathway in SCLC and the differences in utilization and crosstalk between the two pathways remain largely unclear. Here, we found that deletion of the <i>HPRT1</i> gene, which codes for the rate-limiting enzyme of the purine salvage pathway, significantly suppressed tumor growth <i>in vivo</i> in several SCLC cells. We also demonstrated that HPRT1 expression confers resistance to lemetrexol (LMX), an inhibitor of the purine <i>de novo</i> pathway. Interestingly, <i>HPRT1</i>-knockout had less effect on SCLC SBC-5 cells, which are more sensitive to LMX than other SCLC cell lines, suggesting that a preference for either the purine <i>de novo</i> or salvage pathway occurs in SCLC. Furthermore, metabolome analysis of <i>HPRT1</i>-knockout cells revealed increased intermediates in the pentose phosphate pathway and elevated metabolic flux in the purine <i>de novo</i> pathway, indicating compensated metabolism between the <i>de novo</i> and salvage pathways in purine nucleotide biosynthesis. These results suggest that HPRT1 has therapeutic implications in SCLC and provide fundamental insights into the regulation of purine nucleotide biosynthesis.</p>Implications:<p>SCLC tumors preferentially utilize either the <i>de novo</i> or salvage pathway in purine nucleotide biosynthesis, and HPRT1 has therapeutic implications in SCLC.</p></div>