title: ATP13A3 and caveolin-1 as potential biomarkers for difluoromethylornithine-based therapies in pancreatic cancers.
abstract: The purpose of this paper was to better understand the role of polyamine transport in pancreatic cancers.This paper identifies potential biomarkers for assessing the relative tumor commitment to polyamine biosynthesis or transport. Cell lines with low polyamine import activity and low ATP13A3 protein levels appear committed to polyamine biosynthesis and required high concentrations of the polyamine biosynthesis inhibitor, difluoromethylornithine (DFMO) to inhibit their growth (e.g., AsPC-1 and Capan 1). In contrast, cell lines with high polyamine import activity and high ATP13A3 protein expression (e.g., L3.6pl) demonstrated a commitment to polyamine transport and required lower DFMO concentrations to inhibit their growth. Pancreatic cancer cell lines which were most sensitive to DFMO also gave the highest EC50 values for the polyamine transport inhibitors (PTIs) tested indicating that more PTI was needed to inhibit the active polyamine transport systems of these cell lines. Most significant is that the combination therapy of DFMO+PTI was efficacious against both cell types with the PTI showing low efficacy in cell lines with low polyamine transport activity and high efficacy in cell lines with high polyamine transport activity. High ATP13A3 protein expression and moderate to low Cav-1 protein expression was shown to be predictive of tumors which effectively escape DFMO via polyamine import. In summary, this report demonstrates for the first time the role of ATP13A3 in polyamine transport and its use as a potential biomarker along with Cav-1 to select tumors most susceptible to DFMO. These findings may help stratify patients in the ongoing clinical trials with DFMO-based therapies and help predict tumor response.
authors.affiliation: Department of Medical Education, University of Central Florida College of Medicine 12722 Research Parkway, Orlando, Florida 32826, USA.
authors.forename: Meenu
authors.initials: M
authors.lastname: Madan
authors.affiliation: Department of Medical Education, University of Central Florida College of Medicine 12722 Research Parkway, Orlando, Florida 32826, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Medical Education, University of Central Florida College of Medicine 12722 Research Parkway, Orlando, Florida 32826, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Skruber
authors.affiliation: Department of Pediatric Oncology, Erasmus University Medical Center, Dr. Molewaterplein 50 3015 GE Rotterdam, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.affiliation: Burnett School for Biomedical Sciences, University of Central Florida 6900 Lake Nona Blvd., Orlando, FL 32827, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Altomare
authors.affiliation: Department of Medical Education, University of Central Florida College of Medicine 12722 Research Parkway, Orlando, Florida 32826, USA.
authors.forename: Otto Phanstiel
authors.initials: OP
authors.lastname: Iv
keywords: ATP13A3; Difluoromethylornithine (DFMO); pancreatic cancer; polyamine transport; polyamines