Dopamine receptor D2 is correlated with gastric cancer prognosis

Mu, Jian; Huang, Weidan; Tan, Zhen; Li, Maolan; Zhang, Lin; Ding, Qichen; Wu, Xiangsong; Lu, Jianhua; Liu, Yingbin; Dong, Qian; Xu, Haineng

doi:10.3892/ol.2017.5573

Cited by 45 publications

(45 citation statements)

References 25 publications

(25 reference statements)

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“…Other studies have shown that dopamine receptor subtypes play roles in cancer. For example, survival durations of gastric cancer patients with a higher expression of DRD2 are shorter . In a xenograft study using hepatoma cell lines, DRD5 expression is higher in tumors than that in nontumor adjacent tissues and the capacity of tumorigenesis is decreased in thioridazine‐pretreated hepatoma cells .…”

Section: Discussionmentioning

confidence: 99%

Dopamine receptor antagonists induce differentiation of PC‐3 human prostate cancer cell‐derived cancer stem cell‐like cells

et al. 2019

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Background The objective of this study was to determine whether PC‐3 human prostate cancer cell‐derived cancer stem cells (CSC)‐like cells grown in a regular cell culture plate not coated with a matrix molecule might be useful for finding differentiation‐inducing agents that could alter properties of prostate CSC. Methods Monolayer cells prepared from sphere culture of PC‐3 cells were characterized for the presence of pluripotency and tumorigenicity. They were then applied to screen a compound library to find compounds that could induce morphology changes of cells. Mechanisms of action of compounds selected from the chemical library that induced the loss of pluripotency of cells were also investigated. Results C5A cells prepared from PC‐3 cell‐derived sphere culture expressed pluripotency markers such as Oct4, Sox2, and Klf4. C5A cells were highly proliferative. They were invasive in vitro and tumorigenic in vivo. Some dopamine receptor antagonists such as thioridazine caused reduction of pluripotency markers and tumorigenicity. Thioridazine, unlike promazine, inhibited phosphorylation of AMPK in a dose dependent manner. BML‐275, an AMPK inhibitor, also induced differentiation of C5A cells as seen with thioridazine whereas A769663, an AMPK activator, blocked its differentiation‐inducing ability. Transfection of C5A cells with siRNAs of dopamine receptor subtypes revealed that knockdown of DRD2 or DRD4 induced morphology changes of C5A cells. Conclusions Some dopamine receptor antagonists such as thioridazine can induce differentiation of CSC‐like cells by inhibiting phosphorylation of AMPK. Binding to DRD2 or DRD4 might have mediated the action of thioridazine involved in the differentiation of CSC‐like cells.

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Section: Discussionmentioning

confidence: 99%

Dopamine receptor antagonists induce differentiation of PC‐3 human prostate cancer cell‐derived cancer stem cell‐like cells

et al. 2019

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“…249 In gastric cancer, increased expression of D2R negatively correlates with patient survival. 250 Similarly, increased levels of D2R have been detected in samples of cervical, 251 lung, 252 and breast cancer. 253 In preclinical cancer models, dopamine receptors are being studied as potential drug targets.…”

Section: Classical Central Nervous System Neurotransmitters (Dopaminementioning

confidence: 93%

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

Cervantes‐Villagrana

Albores-García

Cervantes-Villagrana

et al. 2020

Sig Transduct Target Ther

138

112

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Normal cells are hijacked by cancer cells forming together heterogeneous tumor masses immersed in aberrant communication circuits that facilitate tumor growth and dissemination. Besides the well characterized angiogenic effect of some tumor-derived factors; others, such as BDNF, recruit peripheral nerves and leukocytes. The neurogenic switch, activated by tumor-derived neurotrophins and extracellular vesicles, attracts adjacent peripheral fibers (autonomic/sensorial) and neural progenitor cells. Strikingly, tumor-associated nerve fibers can guide cancer cell dissemination. Moreover, IL-1β, CCL2, PGE 2 , among other chemotactic factors, attract natural immunosuppressive cells, including T regulatory (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, to the tumor microenvironment. These leukocytes further exacerbate the aberrant communication circuit releasing factors with neurogenic effect. Furthermore, cancer cells directly evade immune surveillance and the antitumoral actions of natural killer cells by activating immunosuppressive mechanisms elicited by heterophilic complexes, joining cancer and immune cells, formed by PD-L1/PD1 and CD80/CTLA-4 plasma membrane proteins. Altogether, nervous and immune cells, together with fibroblasts, endothelial, and bone-marrow-derived cells, promote tumor growth and enhance the metastatic properties of cancer cells. Inspired by the demonstrated, but restricted, power of anti-angiogenic and immune cell-based therapies, preclinical studies are focusing on strategies aimed to inhibit tumor-induced neurogenesis. Here we discuss the potential of anti-neurogenesis and, considering the interplay between nervous and immune systems, we also focus on anti-immunosuppression-based therapies. Small molecules, antibodies and immune cells are being considered as therapeutic agents, aimed to prevent cancer cell communication with neurons and leukocytes, targeting chemotactic and neurotransmitter signaling pathways linked to perineural invasion and metastasis.

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“…There are several reports indicating elevated DRD2 expression in cancer cells compared to normal cells in several cancer types, and DRD2 overexpression correlates with an advanced stage and stemness of cancer and a poor prognosis of patients 7 , 9 , 24 . Moreover, antagonizing DRD2 signaling either by DRD2 antagonists, such as thioridazine and trifluoperazine, or genetic depletion show the proapoptotic, antimetastatic, antiangiogenic, and anticancer stem cell properties in several tumor types 7 , 10 , 25 .…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulated dopamine secretion or inactivation of DRs was reported to correlate with various neurological diseases such as schizophrenia and Parkinson's disease 8 . In addition to the traditional function of DRs in neurological diseases, among DRs, DRD2 especially was reported to be overexpressed in different cancer types, including cervical, lung, pituitary, colon, and gastric cancers and to be correlated with poor prognoses of these cancers 7 , 9 . Moreover, blocking DRD2 was shown to suppress proliferation and induce apoptosis of both cancer cells and cancer stem cells 7 , 10 .…”

Section: Introductionmentioning

confidence: 99%

Dopamine receptor D2 genetic variations is associated with the risk and clinicopathological variables of urothelial cell carcinoma in a Taiwanese population

Tung¹,

Wen²,

Wang³

et al. 2018

Int. J. Med. Sci.

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Dopamine receptor D2 (DRD2) is overexpressed in several kinds of cancers and was correlated with the prognosis of these cancers. Polymorphisms within the DRD2 gene were shown to be associated with lung and colon cancers. The purpose of this study was to explore effects of DRD2 gene polymorphisms on the susceptibility to and clinicopathological characteristics of urothelial cell carcinoma (UCC). In total, 369 patients diagnosed with UCC and 738 healthy controls were enrolled to analyze DRD2 genotypes at four loci (rs1799732, -141C>del; rs1079597, TaqIB; rs6277, 957C>T; and rs1800497, TaqIA) using a TaqMan-based real-time polymerase chain reaction (PCR). We found a significantly lower risk for UCC in individuals with the DRD2 rs6277 CT genotype compared to those with the wild-type CC genotype (adjusted odds ratio (AOR)=0.405, 95% confidence interval (CI): 0.196~0.837, p=0.015). In 124 younger patients (aged < 65 years) of the recruited UCC cohort, patients who carried at least one T allele of DRD2 rs1800497 were at higher risk (AOR=2.270, 95% CI: 1.060~4.860, p=0.033) of developing an invasive stage (pT2~pT4). In 128 female patients of the recruited UCC cohort, patients who carried at least one deletion allele of DRD2 rs1799732 showed a higher incidence of having an invasive stage (AOR=2.585, 95% CI: 1.066~6.264, p=0.032) and a large tumor (AOR=2.778, 95% CI: 1.146~6.735, p=0.021). Further analyses of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets revealed correlations of the expression of DRD2 with an invasive tumor, tumor metastasis, and the lower survival rate in patients with UCC. Our findings suggest that DRD2 levels might affect the progression of UCC, and the polymorphisms rs6277, rs1800497, and rs1799732 of DRD2 are probably associated with the susceptibility and clinicopathologic development of UCC in a Taiwanese population.

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Dopamine receptor D2 is correlated with gastric cancer prognosis

Cited by 45 publications

References 25 publications

Dopamine receptor antagonists induce differentiation of PC‐3 human prostate cancer cell‐derived cancer stem cell‐like cells

Dopamine receptor antagonists induce differentiation of PC‐3 human prostate cancer cell‐derived cancer stem cell‐like cells

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

Dopamine receptor D2 genetic variations is associated with the risk and clinicopathological variables of urothelial cell carcinoma in a Taiwanese population

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