MRP4 as an oncogene in pancreatic cancer: overexpression of MRP4 induces cell proliferation, tumor growth and chemoresistance.

CIUDAD AUTONOMA DE BUENOS AIRES

Congreso; REUNION CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

SOCIEDAD ARGENTINA DE INVESTIGACION CLINICA

Pancreatic duct adenocarcinoma (PDAC) is currently the fourth most frequent cause of cancer-related deaths due to its high resistance to chemotherapy, early metastasis and inclination to recurrence. Even after the emergence of recent new targeted agents and the use of multiple therapeutic combinations, no treatment option is viable in patients with advanced cancer. Thus, the development of novel strategies that target progression of this kind of neoplasia are needed for PDAC to improve its prognosis.MRP4 transports multiple endogenous and exogenous substances and its deregulation has been reported in numerous types of cancers. Recent evidence from our lab shows that the activity of the transporter, mainly the efflux of AMPc, is critical for cell proliferation, in culture and in vivo, and its inhibition causes a clear decrease in malignancy and invasive capacity. These findings suggest that MRP4could bean attractive therapeutic target in PDAC. However, the role of MRP4 as mediator in pancreatic tumor progression remains still controversial.The aimof this study was to investigate the role of MRP4 in pancreatic cancer progression and chemoresistance. We used the BxPC-3 pancreatic cell line as a model which lacks de typicalk-ras pancreatic mutation and established two clones which overexpress MRP4 significantly (MRP4-G6 and MRP4-H7), compared to the control cell line (empty-C4).Western blot and qPCR assays confirmed higher MRP4 protein and mRNA levels, respectively. MRP4 overexpression confers a higher proliferative rate (p<0.001) and lower duplication time in the BxPC-3 clones (C4: 41.00± 5.67; G6: 28.70±4.55; H7: 29.52± 0.95). Moreover, this proliferative advantage was maintained inin vivo xenografts using NSG mice (p<0.01). Treatment with two different MRP4 inhibitors, MK-571 and Ceefourin-1, impaired cell proliferation of control as well as MRP4-overexpressing clones (p<0.01 at 50 µM). Interestingly, although MRP4 does not transport 5-Fluoruracil (5-FU), H7 cells display a higher tolerance to this agent compared to control cells (p<0.05). Our results suggest that up-regulation of MRP4 could represent an adaptive advantage and is associated to poor prognosis, evidenced by higher cell proliferation and resistance to 5-FU treatment in a pancreatic cancer model. Finally, we propose that MRP4 levels could serve as a biomarker to predict resistance and that targeting MRP4 could improve chemotherapy response in these patients.