Roles Of Dopamine Receptor D₂ Subtypes Mediated Signaling In The Development Of Lung Cancer

lung cancer is the first most common diagnosed cancer and the leading cause of cancer-related death.More and more young people are getting sick,which has become a major threat to human health.At present,there is no radical cure for lung cancer.Surgical treatment is often used in the early stage to prolong the survival time,but there is no obvious abnormality in the early stage of lung cancer and it is difficult to detect.Non-small cell lung cancer（NSCLC）is the most common type of lung cancer.The common means of advanced lung cancer is drug targeted therapy.Currently,the main target of drugs for the treatment of NSCLC is epidermal growth factor receptor（EGFR）,but it is limited to adapt to the narrow population.Therefore,it is particularly important to study the potential mechanism of the occurrence and development of NSCLC and to find new therapeutic targets.GPCR regulates many physiological activities of the human body and is an important drug target.Now,about 33% of clinical drugs directly act on GPCRs,which is the largest protein family in humans.Among them,D₂ occupies an important position,with long(D_2L)and short(D_2S)receptor subtypes.It mediates cell secretion and cell viability and is an important drug target.D₂ has been found in many tumors,and its agonist has the function of inhibiting tumor growth.The association between D₂ and lung cancer has been shown in many literatures.In lung cancer,D₂ is reduced.Enhancing D₂ expression can increase survival time and improve poor prognosis.In this study,we constructed two receptor subtypes,D_2L and D_2S,and focused on them to investigate their potential molecular mechanisms in the development of lung cancer.Through studies,we found that after the overexpression of D_2L and D_2S in A549 lung cancer cells,c AMP levels were decreased,the expressions of BCL-2,BCLXL and other cell apoptosis inhibitors were down-regulated,suggesting that D_2S and D_2L may promote the apoptosis of lung cancer cells by inhibiting BCL-2 and BCLXL.At the same time,overexpression of D₂ can inhibit TNFα,Stat3,Clycin D1,IL-6 and other tumor-related inflammatory factors,suggesting that D₂ may play a role by inhibiting the inflammatory response in cells.Meanwhile,Western blotting assay showed that overexpression of D₂ could block the NF-κB signaling pathway,reduce the proliferation rate of A549 cells,inhibit the ability of clone formation,invasion and migration,and the effect of D_2L was stronger than that of D_2S,which further suggested the possibility of D₂ as a therapeutic target for lung cancer.In addition,we also used the laboratory’s drug screening platform to study the activation of D₂ by the active ingredients in the Yunnan characteristic Chinese herbal medicine gastrodin,and discovered two natural active ingredients that can activate the D₂ target: gastrodin and vanillin.Hope to explore new ideas for the treatment of lung cancer and bring new dawn to patients with lung cancer.