Mechanistic Investigation of DRD1 and EGFR as a Novel Signaling Axis in Lung Cancer

Authors

• LB Toulabi
• K Lee
• A Zingone
• BM Ryan

Abstract

The dopamine pathway (DAP) mediates several processes in the central nervous system, including voluntary movement, reward, sleep, attention, memory and learning. The physiological functions of dopamine are mediated through its interaction with a class of G protein-coupled receptors, DRD1-DRD5. Our group discovered a 3' UTR SNP in DRD1 and lower risk of developing lung cancer in individuals exposed to secondhand smoke during childhood. Other groups have reported that there is lower incidence of certain cancers, especially lung cancer, in patients with diseases that involve DAP, such as Parkinson’s disease. Furthermore, several agnostically designed molecular biology-based studies have identified drugs targeting DAP as potent anti-cancer drugs in solid tumors. We hypothesize that the DAP may play a novel role in the pathogenesis of lung cancer. We generated stable lung cancer cell lines harboring shRNA-mediated knockdown of DRD1, and cell lines with stable DRD1 overexpression which display increased and decreased growth, respectively. This data infers a tumor suppressive role for DRD1 in lung cancer. To understand the mechanistic basis for tumor suppressive role of DRD1, we aimed to determine which signaling pathways are modulated by DRD1 activation/reduction. Therefore, we analyzed global phosphorylation levels of up to 100 proteins on our in-house DRD1 cell line models by high-throughput Kinome profiling. We also investigate transcriptional changes associated with DRD1 downregulation/overexpression by Transcriptional Profiling. Kinome and Transcriptional profiling analysis results collectively suggest that DRD1 reduction is associated with EGFR and MAPK signaling activation. Our preliminary data confirms the role of DRD1 in MAPK signaling. Our western blot analysis shows that over expression of DRD1 in H1299 lung cancer cell line decreases ERK1/2 activation. In addition, immunofluorescent staining of H1299 cell lines suggests that EGFR and DRD1 may colocalized. As EGFR is a key protein in lung cancer development, prognosis, and resistance to EGFR inhibitor treatments is a big challenge for treating lung cancer. Therefore, understanding the molecular and cellular basis of DRD1 and EGFR and MAPK signaling interaction is important to develop potentially more effective molecular therapeutic approaches that involve simultaneously targeting both DRD1 and EGFR.

Scientific Focus Area: Cancer Biology

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