PYCR1 promotes the malignant progression of lung cancer through the JAK-STAT3 signaling pathway via PRODH-dependent glutamine synthesize

by Selleckchem | May 18 2023

Background: Lung cancer is a serious threat to human life. It is of great significance to elucidate the pathogenesis of lung cancer and search for new markers. This study evaluate the clinical value of pyrroline-5-carboxylate reductase 1 (PYCR1) and explore its role and mechanisms in the malignant progression of lung cancer.

Methods: PYCR1 expression and its relationship with prognosis were analyzed using a bioinformatics database. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were utilized to examine the expression of PYCR1 in lung cancer tissues and peripheral blood. PYCR1-overexpressing lung cancer cells were constructed, then the cell proliferative, migration, and invasion ability was examined by the MTT and Transwell assays. siRNA against PRODH and STAT3 inhibitor sttatic was used to further elucidate the underlying mechanisms. Luciferase and CHIP assays were carried out for validate the how PYCR1 regulated PD-L1 expression via STAT3. Xenograft experiment was performed to determine the role of PYCR1 in vivo.

Results: Database analysis showed that PYCR1 expression was significantly increased in lung cancer tissues, and its high expression predicted poor prognosis. Lung cancer tissue and peripheral blood of patients showed obviously increased PYCR1 expression, and the sensitivity and specificity of serum PYCR1 in the diagnosis of lung cancer were 75.7% and 60%, respectively. PYCR1 overexpression enhanced the proliferative, migration, and invasion abilities of lung cancer cells. Both PRODH silence and stattic effectively attenuated the function of PYCR1. Animal experiment and IHC data indicated that PYCR1 could activated STAT3 phosphorylation and PD-L1, as well as suppressed T cell infiltration in lung cancer. Finally, we also validated that PYCR1 promoted PD-L1 transcription by elevating STAT3 binding to the gene promoter.

Conclusion: PYCR1 has certain value in the diagnosis and prognosis of lung cancer. Moreover, through regulating JAK-STAT3 signaling pathway, PYCR1 significantly participated in process of lung cancer progression via the metabolism link between proline and glutamine, indicating that PYCR1 might be also a novel therapeutic target.

Comments：

This study evaluated the clinical significance and potential mechanisms of pyrroline-5-carboxylate reductase 1 (PYCR1) in the pathogenesis of lung cancer. Through bioinformatics analysis, it was found that PYCR1 expression was significantly increased in lung cancer tissues, and its high expression was associated with poor prognosis. The study also showed that PYCR1 expression was elevated in the peripheral blood of lung cancer patients, and the sensitivity and specificity of serum PYCR1 in the diagnosis of lung cancer were 75.7% and 60%, respectively.

Furthermore, in vitro experiments demonstrated that PYCR1 overexpression enhanced the proliferation, migration, and invasion of lung cancer cells. Mechanistic investigations revealed that PYCR1 activated STAT3 phosphorylation and PD-L1 expression, while inhibiting T cell infiltration in lung cancer through regulating the JAK-STAT3 signaling pathway. Animal experiments confirmed the pro-tumorigenic role of PYCR1 in lung cancer.

Overall, these findings suggest that PYCR1 has significant clinical value in the diagnosis and prognosis of lung cancer, and may serve as a potential therapeutic target for lung cancer treatment through targeting the metabolism link between proline and glutamine via the JAK-STAT3 pathway.