MP51-07 LOSS OF EPHRIN SIGNALING ALTERS THE LIPID RHEOSTAT ASSOCIATED WITH PROSTATE CANCER RACIAL DISPARITIES

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II (MP51)1 Apr 2020MP51-07 LOSS OF EPHRIN SIGNALING ALTERS THE LIPID RHEOSTAT ASSOCIATED WITH PROSTATE CANCER RACIAL DISPARITIES Alejandro Morales, Victoria Gil, Susan Crawford, Simon Hayward, and Omar Franco* Alejandro MoralesAlejandro Morales More articles by this author , Victoria GilVictoria Gil More articles by this author , Susan CrawfordSusan Crawford More articles by this author , Simon HaywardSimon Hayward More articles by this author , and Omar Franco*Omar Franco* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000913.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The presence of abdominal central obesity in prostate cancer (PCa) patients is associated with aggressive tumors. Compared to Caucasians (CA), African American (AA) men are at highest risk of developing and dying from PCa. The Center for Disease Control reports racial disparities in adult obesity (38.4% AA vs. 28.6% in CA). In an obese environment, cancer cells store fatty acids in lipid droplets (LD), composed of triacylglycerols (TAG) and cholesterol esters, which can be used as an energy source to sustain proliferation and migration. Decreased gene expression of members of the ephrin family have been linked to PCa-RD. Here we show the functional consequences of aberrant ephrin signaling in lipid metabolism on PCa tumorigenesis in AA compared to CA. METHODS: The density and size of LD were quantified in PCa specimens from different racial backgrounds. EPHB2 signaling was manipulated in PCa cells using siRNA and CRISPR approaches. LD were quantified under basal and obesogenic (added oleic acid) environments. Molecules involved in TAG metabolism were assessed. The effects of EPHB2 loss on PCa cells growth and local invasion was tested in vitro and in vivo. RESULTS: LD density increased in high grade tumors. Under obesogenic conditions, PCa cells from AA showed increased proliferation compared to CA. Loss of EPHB2 increased the tumorigenicity of PCa cells. Quantification of LD profiles showed racial differences. Alteration of EPHB2 led to differential expression of TAG-associated molecules DGAT1, DGAT2 and ATGL in AA compared to CA. Targeting key TAG molecules associated with EPHB2-induced effects reduced the tumorigenicity of PCa cells. Centrosome amplification and microtubule organizing center (MTOC) were associated with lipid metabolic changes in cells with decreased EphB2 signaling. CONCLUSIONS: Loss of EPHB2 signaling in PCa cells triggers aberrant lipid metabolism leading to excessive accumulation of LD. Because loss of ephrin signaling is associated with PCa-RD, this lipid-rich energy status may serve as a source of energy to fuel a more aggressive phenotype observed in AA. Several TAG inhibitors are currently being evaluated in clinical trials as anti-obesity agents. The potential of these drugs to elicit anti-tumorigenic utility in patients with altered ephrin levels requires further study. Source of Funding: R01 CA242920-01 © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e766-e766 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alejandro Morales More articles by this author Victoria Gil More articles by this author Susan Crawford More articles by this author Simon Hayward More articles by this author Omar Franco* More articles by this author Expand All Advertisement PDF downloadLoading ...