DIFFERENTIAL REGULATION OF MULTIDRUG RESISTENCE ASSOCIATED PROTEIN 4 (MRP4/ABCC4) IN HUMAN PANCREATIC DUCTAL ADENOCARCINOMA AND HEPATOCELUALAR CELL LINES.

BAZZI, ZAHER; JULIETA ALLEGRO; RODRIGO LAGOS; NATALIA GOMÉZ; ISMAEL BAROSSO; CARLOS DAVIO; CAROLINA GHANEM

Congreso; Sociedad Argentina de Investigación Clínica; 2023

Multidrug resistance associated protein 4 (MRP4/ABCC4) and epidermal growthfactor receptor (EGFR) are associated to the poor overall survival in Hepatocellularcarcinoma (HCC) and pancreatic ductal carcinoma (PDAC). Also, overexpressionof both proteins are associated with high cell proliferation in several types ofcancer. Our previous results show that EGF induces MRP4 expression in apancreatic cell line, BxPC3. The aim of this work is to evaluate the effect of EGF onMRP4 expression using human cancer cell lines, BxPC3 and HEPG2, that differ intheir basal expression of EGFR. The expression of EGFR was detected only inBXPC3 but not in HEPG2 by western blot (WB). To confirm this result, westimulate both cell lines with EGF, the canonical agonist of the receptor andevaluate the activation measuring P-JNK/JNK relation by WB.  After 5 minutes ofexposure the pathway was activated in both cell lines. However, the magnitude ofresponse was significantly higher in BxPC3 compared to HEPG2. Additionally, wedemonstrated that EGF (0.3 ng/ul) induces the transcriptional expression of MRP4only in BxPC3, increasing its mRNA and protein level at 24 and 48 hoursrespectively, with no modification of its expression in HEPG2. Finally, the inductionof MRP4 was abolished in the presence of a selective EGFR inhibitor (CL 387-785;1µM). Furthermore, the basal expression of MRP4 is also associated with the levelof EGFR expression, being higher in the PDAC line and lower in HEPG2. Insummary, these data demonstrate that the level and activation of EGFR isassociated with the induction of MRP4 expression in vitro. Additionally, it is knownthat PGE2, a typical substrate of MRP4 transactivate EGFR, probably suggest thatboth PDAC and HCC poor prognosis markers could be co-regulated, enhancingtheir effect upon each other.