Dopamine (DA, 3-hydroxytyramine) is 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 (DAP) 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 (TME) 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.

The heat shock response (HSR) is a cellular stress response that senses protein misfolding and restores protein folding homeostasis, or proteostasis. We previously identified an HSR regulatory network in Caenorhabditis elegans consisting of highly conserved genes that have important cellular roles in maintaining proteostasis. Unexpectedly, the effects of these genes on the HSR are distinctly tissue-specific. Here, we explore this apparent discrepancy and find that muscle-specific regulation of the HSR by the TRiC/CCT chaperonin is not driven by an enrichment of TRiC/CCT in muscle, but rather by the levels of one of its most abundant substrates, actin. Knockdown of actin subunits reduces induction of the HSR in muscle upon TRiC/CCT knockdown; conversely, overexpression of an actin subunit sensitizes the intestine so that it induces the HSR upon TRiC/CCT knockdown. Similarly, intestine-specific HSR regulation by the signal recognition particle (SRP), a component of the secretory pathway, is driven by the vitellogenins, some of the most abundant secretory proteins. Together, these data indicate that the specific protein folding requirements from the unique cellular proteomes sensitizes each tissue to disruption of distinct subsets of the proteostasis network. These findings are relevant for tissue-specific, HSR-associated human diseases such as cancer and neurodegenerative diseases. Additionally, we characterize organismal phenotypes of actin overexpression including a shortened lifespan, supporting a recent hypothesis that maintenance of the actin cytoskeleton is an important factor for longevity.

Dopamine (DA) signaling contributes to a variety of physiologic processes in the central nervous system (CNS), including voluntary movement, reward, sleep, attention, memory and learning. However, emerging work highlights the importance of the DA pathway in non CNS-related functions, including regulation of the cardiovascular, olfactory, endocrine, and immune systems. Recently, our group discovered and replicated an epidemiologic association between an SNP in the 3’ UTR of the DRD1 (dopamine receptor D1) gene and risk of developing lung cancer. Although dopamine mediates nicotine addiction, the association was also observed in never-smokers, suggesting that DRD1 may be directly involved in lung cancer pathogenesis. As there are sparse data regarding the DAP in normal lung, we initially characterized dopamine signaling (receptors, transporters, metabolizing enzymes, synthesis) in the proximal and distal regions of the normal lung. Our results show that the DAP, including DRD1, is expressed throughout the pulmonary system. In lung cancer, DRD1 expression is lost in a majority of cases—most likely due to aberrant methylation—such that patients with high expression have significantly better survival. We generated stable lung cancer cell lines harboring shRNA-mediated knockdown of DRD1 and stable DRD1 overexpression. Downregulation of DRD1 significantly increased cell proliferation as well as xenograft tumor formation, while overexpression of DRD1 led to a suppression of cell growth. Using transcriptome, kinome and phosphoproteome arrays, we also discovered that modulation of DRD1 expression specifically modulates EGFR phosphorylation and MAPK/ERK signaling. Moreover, confocal analyses show that DRD1 co-localizes with EGFR at the cell membrane, suggesting that this could be a direct interaction. Although DRD1 has been linked with regulation of inflammation, we have not find significant similar evidence in this study to date. Our work highlights a novel aspect of DRD1 singaling in the context of lung cancer and possibly normal pulmonary physiology. This study could lead to the identification of novel oncotargets, biomarkers and therapeutic strategies for tumors involving EGFR signaling or mutations in lung cancer. These data also contribute to a preclinical rationale for repositioning FDA-approved antidepressants as adjunct therapeutics with chemotherapy and may have significant translational impact for some lung cancer patients. Indeed, our recent findings show that antidepressants—specifically NDRIs (norepinephrine and dopamine reuptake inhibitors)—have better outcomes. Citation Format: Leila Toulabi, Conor Bradley, Adriana Zingone, Christopher Grant, Oscar Vidal, Khadijah Mitchell, Brid M. Ryan. Regulation of EGFR signaling by DRD1 in lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A34.