Understanding the role of dopamine in cancer: past, present and future

Abstract

Dopamine (DA, 3-hydroxytyramine) is a member of the catecholamine family and is classically characterized according to its role in the central nervous system as a neurotransmitter. In recent decades, many novel and intriguing discoveries have been made about the peripheral expression of DA receptors (DRs) and the role of DA signaling in both normal and pathological processes. Drawing from decades of evidence suggesting a link between DA and cancer, the DA pathway has recently emerged as a potential target in antitumor therapies. Due to the onerous, expensive and frequently unsuccessful nature of drug development, the repurposing of dopaminergic drugs for cancer therapy has the potential to greatly benefit patients and drug developers alike. However, the lack of clear mechanistic data supporting the direct involvement of DRs and their downstream signaling components in cancer represents an ongoing challenge that has limited the translation of these drugs to the clinic. Despite this, the breadth of evidence linking DA to cancer and non-tumor cells in the tumor microenvironment justifies further inquiry into the potential applications of this treatment modality in cancer. Herein, we review the literature characterizing the interplay between the DA signaling axis and cancer, highlighting key findings, and then propose rational lines of investigation to follow.

Figure 1.

Targeting the dopamine pathway in tumor cells. Upper left: schematic of a solid tumor with tumor cells and associated non-tumor cells. (A) Description of compounds in development that promote cell death as their primary mechanism of action. (B) Description of compounds in development that inhibit cell proliferation as their primary mechanism of action. Image created with Biorender.com.

Figure 2.

Targeting the dopamine pathway in the tumor microenvironment. Note: For a detailed discussion of the interactions between DA signaling and the immune system, including the mechanisms depicted in this figure, please refer to section S2.0 of the Supplementary Material. Upper left: Schematic of a solid tumor with tumor cells and associated non-tumor cells. (A) DA treatment inhibits angiogenesis by reducing VEGF signaling and ERK phosphorylation in endothelial cells. (B) DRD1 agonism with dihydrexidine regulates YAP/TAZ signaling in lung fibroblasts to reverse idiopathic pulmonary fibrosis. (C) Treating regulatory T cells with DRD1 agonist, SKF-38393, upregulates cAMP production and reduces their immunosuppressive regulation of effector T cells. (D) Activation of DRD4 on CD4 T cells via DA treatment increases production of IL-2 and STAT-5, and promotes their differentiation to T-helper 2 phenotype. (E) Treatment of colorectal cancer cells with DRD2 antagonist, TFP, increased PD-L1 expression in vitro and in vivo. TFP treatment also increased PD-1 expression on tumor-infiltrating T cells. (F) DA treatment inhibits NLRP3 inflammasome activation in macrophages and reduces systemic inflammation in mice, both in a DRD1-dependent manner. DA treatment also reduces production of the proinflammatory cytokine, TNF-α, in macrophages. (G) ONC201 treatment represses oxidative phosphorylation in macrophages and promotes secretion of IL-1B and TNF-α. (H) Activation of DRD4 on tumor-associated macrophages (TAMs) via DA treatment reduces the secretion of protumor cytokines and reduces the tumor-protective effects associated with the M2 phenotype. (I) Treating microglia with isosibiricin increased expression of DRD1 and DRD2 and reduced activation of the NLRP3 inflammasome. (J) Activation of DRD5 on dendritic cells via DA treatment increased secretion of IL-12 and IL-13, and also inhibited CD4 T-cell activation and IL-2 production. (K) Treatment with DA and SKF-38393 inhibited myeloid-derived suppressor cell activity, as measured by nitric oxide production, proliferation and inhibition of CD8 T-cell interaction with tumor cells. Image created with Biorender.com.