Progestin receptor promotes cell macropinocytosis through CDC42 in pancreatic cancer

Endocrine receptors play an essential role in tumor metabolic reprogramming and represent a potential therapeutic approach in pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by a nutrient-deprived microenvironment, and to support their energetic needs, they can internalize extracellular proteins via macropinocytosis. In this study, we found that progesterone receptor (PGR), a steroid-responsive nuclear receptor, has a higher expression in PDAC tissues from patients and transgenic LSL-KrasG12D/+; LSL-Trp53R172H/+; PDX1-cre (KPC) mice. Moreover, PGR knockdown restrained PDAC cell survival and tumor growth both in vitro and in vivo. Genetic and pharmacological PGR inhibition resulted in dramatically macropinocytosis impairment in PDAC cells and subcutaneous tumor models, which indicates involvement of this receptor in macropinocytosis regulation. Mechanistically, PGR deficiency caused a subsequently decreased expression of CDC42, a key regulator in macropinocytosis. These data deepen our understanding of how endocrine system influences tumor progression via non-classical pathway and provide a novel therapeutic option for patients with PDAC. The cDNA microarrays were performed to investigate the differentially expressed cDNA in PGR-interference AsPC-1 cells compared to control cells.