Overexpressed D2 Dopamine Receptor Inhibits Non-Small Cell Lung Cancer Progression through Inhibiting NF-κB Signaling Pathway

Abstract

Background/aims: Non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide. Dopamine receptor D2 (DRD2) has multiple roles in clinical progression of NSCLC and functional maintenance of cancer cells. However, little is known about the molecular mechanism. Here, we clarified whether DRD2 inhibits lung cancer progression and identified the underlying downstream signaling.

Methods: DRD2 mRNA and protein levels were detected in clinical specimens by qRT-PCR and immunohistochemistry, respectively. MTT and colony formation assays were applied to analyze cell proliferation. The underlying molecular mechanism was identified by dual luciferase, western blot, qRT-PCR, cAMP detection, immunoprecipitation, and chromatin immunoprecipitation assays. A murine NSCLC model was used to clarify the role of DRD2 in tumor cell proliferation.

Results: We found that DRD2 ablated tumor cell growth. DRD2 expression in NSCLC tissues was lower than in adjacent normal lung tissues. Moreover, DRD2 mRNA and protein levels in NSCLC were negatively correlated with the tumor size, TNM status, and patient overall survival. In vitro experiments showed that disruption of DRD2 promoted the proliferation of NSCLC cell lines A549 and SK-MES-1 by inhibiting the NF-κB signaling pathway. Furthermore, DRD2 overexpression not only blocked lipopolysaccharide-induced A549 and SK-MES-1 cell proliferation and growth, but also inhibited the tumorigenesis in murine xenograft models.

Conclusion: These results indicate that DRD2 may be a potential therapeutic target for lung cancer patients with high DRD2 expression by ablating the NF-κB signaling pathway.

Keywords: DRD2; Growth; NF-κB signaling pathway Clinic outcome; NSCLC; Proliferation.