Targeting the Prolactin Receptor Signaling Using an Antipsychotic Drug to Suppress Pancreatic Cancer

Abstract

Pancreatic cancer (PCa) is deadly cancer with an abysmal five‐year survival rate of < 6%. PCa has a bad prognosis and is associated with resistance to standard of care chemotherapeutic gemcitabine and high recurrence rate after surgery. Unfortunately, gemcitabine remains the drug of choice for metastatic pancreatic adenocarcinoma, with minor improvements in survival rate. Hence, there is a need for novel therapeutic interventions for the treatment of PCa. Here we report that prolactin receptor (PRLR) is overexpressed in both PCa tissues and in cell lines. When it is bound by the ligand prolactin (PRL), various downstream events such as JAK‐STAT and ERK‐MAPK signaling pathways are activated. In PCa cell lines, PRL treatment induced dose‐ and time‐dependent STAT3, and ERK1/2 phosphorylation. Moreover, while PRL did not affect PCa cell proliferation, it significantly enhanced pancosphere formation suggesting that PRL affects stem cells. We manipulated PRLR levels using the CRISPR/Cas9 system. This resulted in the lower colony and spheroid formation capacity, decreased migration in vitro as well as reduced tumor‐forming capacity in an orthotopic model of PCa in C57BL/6 mice. Based on these results, we propose that PRL signaling is a novel target for therapeutic intervention. Currently, there are no known small molecules targeting PRL‐PRLR signaling, and X‐ray crystal structure of the intracellular domain of PRLR is not available. Hence, we obtained a homology model for the C‐terminal intracellular region of the receptor and performed a virtual screening for small molecules in silico. In this, we demonstrated that penfluridol (a first‐generation antipsychotic drug) interacts with the JAK2 binding site of the receptor. Penfluridol is known for its long half‐life and is used in the treatment of chronic schizophrenia. We experimentally confirmed binding of penfluridol to PRLR in the cells by using the cellular thermal shift assay (CETSA). Penfluridol treatment decreased PRL‐induced STAT3 and ERK phosphorylation, spheroid formation as well as the migration of PCa cells. We observed a significant increase in autophagy based on increased levels of LC3B, p62 and enhanced expression of autophagy‐related genes ATG‐5, −7 and −12 after penfluridol treatment. Penfluridol treatment also significantly decreased tumor burden in orthotopic PCa model and induced the expression of autophagic related proteins. Taken together, these results suggest that PRL‐PRLR signaling is important for PCa growth and repurposing penfluridol to target PRL‐signaling an effective therapeutic targeting strategy for treating the disease.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.