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.

Drug Use and Cancer Risk: A Drug-Wide Association Study (DWAS) in Norway

“…Overexpression of D2 receptors was found to inhibit growth in non-small cell lung cancer cell lines [34], and D2-receptor agonists abrogated lung tumor progression in human xenograft murine models [35].…”

miR-149* Suppresses Liver Cancer Progression by Down-Regulating Tumor Necrosis Factor Receptor 1–Associated Death Domain Protein Expression

“…43 Blocking the NF-kB pathway can alleviate and even prevent disease development and deterioration. 44,45 miR-149* has anti-inflammatory properties in vitro and in vivo. 13 The present results reveal that miR-149* prevents the phosphorylation of IkBa and NF-kB transactivity.…”

In Vitro Effect and Mechanism of Action of Ergot Alkaloid Dihydroergocristine in Chemoresistant Prostate Cancer Cells

“…Activation of NF-ĸB signaling pathway promotes PCa progression and significantly correlates with advanced diseases (72). It has been shown that DRD2 activation suppresses nuclear translocation of NF-ĸB in the intracerebral hemorrhage mouse model, and DRD2 depletion retards non-small cell lung cancer progression through the inhibition of NF-ĸB (54,55). NF-ĸB transcriptionally activates the expression of multiple oncogenic factors, including anti-apoptotic proteins survivin and Mcl-1 (73,74).…”

“…The effect of DHECS on other putative dopamine receptor-mediated signaling pathways was also investigated (53)(54)(55). DHECS reduced the phosphorylation of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) at Ser511 and increased the phosphorylation of 5'-AMP-activated protein kinase (AMPK) at Thr172 in a time-dependent manner ( Figure 4A), indicating that DHECS may also activate AMPK and augment its function as a tumor suppressor in chemoresistant PCa cells.…”