Small cell lung cancer (SCLC) is a devastating subtype of lung cancer, and its biological, clinical and genetic characteristics differ from those associated with non-small cell lung cancer. Despite the comprehensive genetic analysis of SCLC, promising therapeutic targets have yet to be identified. However, there is growing evidence to support that the cellular metabolic system contributes decisively to malignancy in SCLC.
We applied in vitro proteome-assisted multiple reaction monitoring for protein absolute quantification (iMPAQT), which can allow absolute quantification of 342 metabolic enzymes. Frozen samples obtained from 36 patients with surgically resected SCLC (n = 12), adenocarcinoma (ADC; n = 12) and squamous cell carcinoma (SCC; n = 12) were analyzed by iMPAQT. An enrichment analysis was used to identify metabolic pathways specifically varying in SCLC. One-way ANOVA was used to compare the enzyme expression levels among the three groups. P-value of <0.05 were considered to indicate statistical significance.
The iMPAQT analysis revealed a definitive difference in the absolute amount of the metabolic enzymes between SCLC, ADC and SCC. The purine metabolic pathway was the most upregulated pathway among the metabolic pathways that specifically vary in SCLC (P = 1.1 x 10-10). Among enzymes associated with purine metabolism, only hypoxanthine guanine phosphoribosyltransferase 1 (HPRT1), a key enzyme for the salvage pathway of purine metabolism, was significantly overexpressed in SCLC in comparison to ADC and SCC (P = 2.0 x 10-6). The higher expression of HPRT1 was significantly associated with a larger tumor size (P = 2.0 x 10-3) and poorer overall survival in patients with SCLC (P = 7.9 x 10-3).
The current study showed that purine metabolic enzymes, especially HPRT1, were significantly upregulated in SCLC in comparison to ADC and SCC. Furthermore, the absolute amount of HPRT1 was larger in SCLC patients with larger tumors and a poor prognosis. These results suggest that HPRT1 may be associated with the tumorigenesis of SCLC and contribute to the acquisition of malignant traits, which should be clarified by the further experimental analyses at the molecular level.
Clinical trial identification
Legal entity responsible for the study
Takeda Science Foundation; Clinical Research Promotion Foundation.
All authors have declared no conflicts of interest.