This study reveals that GPR54 regulates non-small cell lung cancer (NSCLC) development via DDC, involving the Gαq/11/AKT and β-arrestin/ERK signaling pathways, providing novel diagnostic and therapeutic targets for NSCLC.
Literature Overview
The article titled 'GPR54 regulates non-small cell lung cancer development via dopa decarboxylase,' published in Signal Transduction and Targeted Therapy, reviews and summarizes the regulatory role of GPR54 in the development of non-small cell lung cancer (NSCLC) and its underlying molecular mechanisms. The study demonstrates that GPR54 influences NSCLC cell proliferation and metabolism through dopa decarboxylase (DDC), involving the Gαq/11/AKT and β-arrestin/ERK signaling pathways, with its regulation of tumor growth validated in mouse models. Additionally, deletion of GPR54 significantly induces tumor cell apoptosis, highlighting its potential as a diagnostic biomarker and therapeutic target. The study further shows that combined targeting of GPR54 and DDC synergistically suppresses NSCLC growth, offering new insights for clinical therapeutic strategies.Background Knowledge
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is a leading cause of cancer-related mortality. Although targeted therapies and immunotherapies have significantly improved outcomes for some patients, drug resistance and the lack of effective targets remain clinical challenges. GPR54, a member of the G protein-coupled receptor (GPCR) family also known as KISS1R, has been reported to play dual roles in various cancers: suppressing metastasis in some contexts while promoting primary tumor development in others. Its function in NSCLC remains unclear. Dopa decarboxylase (DDC), an enzyme that catalyzes the synthesis of dopamine and serotonin, is commonly used as a biomarker for neuroendocrine tumors and is highly expressed in small cell lung cancer, but its role in NSCLC has not been systematically investigated. Recently, metabolic reprogramming has been recognized as a hallmark of cancer, and GPR54 has been implicated in regulating cancer cell metabolism. This study focuses on the functional link between GPR54 and DDC in NSCLC, systematically dissecting the role of this signaling axis in tumorigenesis using transgenic mouse models, cell-based experiments, and transcriptomic analyses, thereby filling a critical gap in the field and providing a theoretical basis for developing GPR54 pathway-targeted therapeutic strategies for NSCLC.
Research Methods and Experiments
The study employed a KrasG12D-driven genetically engineered mouse model (GEMM), inducing lung cancer via intratracheal injection of adenovirus CMV-Cre, with conditional knockout of Gpr54 in the Gpr54flox/flox background to assess its impact on tumor development. Immunohistochemistry, TUNEL assays, and Western blotting were used to evaluate cell proliferation and apoptosis. Gene silencing of GPR54 was performed in multiple human NSCLC cell lines to assess its effects on cell proliferation, colony formation, and apoptosis. RNA sequencing was conducted to analyze transcriptomic changes upon Gpr54 deletion, with a focus on glycolysis and DDC expression. Seahorse technology was used to measure oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and proton efflux rate (PER) to evaluate glycolytic function. Various signaling pathway inhibitors (e.g., FR900359, LY294002, rapamycin) and agonists (kisspeptin-10) were used to investigate downstream signaling mechanisms of GPR54. Functional validation of DDC in NSCLC cells was performed through gene silencing and pharmacological intervention (carbidopa), and the therapeutic efficacy of combining KP234 with carbidopa was tested.Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to reveal the critical role of the GPR54-DDC signaling axis in NSCLC development, expanding our understanding of GPR54 in cancer beyond metastasis suppression to include metabolic reprogramming and proliferation control in primary tumors. This pathway offers novel diagnostic biomarkers and therapeutic targets for NSCLC, particularly as high expression of GPR54 and DDC correlates with poor patient prognosis, suggesting clinical relevance.
Future studies should further explore the heterogeneity of the GPR54-DDC signaling axis across different NSCLC subtypes and validate its therapeutic potential in patient-derived organoids or PDX models. Moreover, carbidopa, an already approved drug, offers a rapid translational path for repurposing in NSCLC treatment. Combination targeting of GPR54 and DDC may overcome resistance to existing targeted therapies and warrants in-depth evaluation in preclinical models.
Conclusion
This study systematically elucidates the oncogenic role of GPR54 in non-small cell lung cancer and its underlying molecular mechanisms. It demonstrates that GPR54 upregulates dopa decarboxylase (DDC) expression by activating the Gαq/11-PI3K/AKT-mTOR signaling pathway, which in turn maintains NF-κB activity, forming a positive feedback loop that promotes tumor cell proliferation and glycolytic metabolism. Deletion or inhibition of GPR54 significantly induces tumor cell apoptosis and suppresses tumor growth. Furthermore, DDC, as a downstream effector, effectively blocks NSCLC progression when silenced or pharmacologically inhibited. Notably, the combination of KP234, a GPR54 antagonist, and the DDC inhibitor carbidopa exhibits synergistic anti-tumor effects, suggesting the feasibility of a novel combination therapy strategy. These findings not only uncover the pivotal role of the GPR54-DDC signaling axis in NSCLC but also provide a solid foundation for developing new diagnostic markers and therapeutic approaches, holding significant translational medical value.
