140 ERP46 MEDIATES KIDNEY CANCER TUMORIGENESIS BY INHIBITING ADIPONECTIN TUMOR SUPPRESSIVE EFFECTS

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research I1 Apr 2012140 ERP46 MEDIATES KIDNEY CANCER TUMORIGENESIS BY INHIBITING ADIPONECTIN TUMOR SUPPRESSIVE EFFECTS Wilhelmina C. Duivenvoorden, Jian-Ping Lu, and Jehonathan H. Pinthus Wilhelmina C. DuivenvoordenWilhelmina C. Duivenvoorden Hamilton, Canada More articles by this author , Jian-Ping LuJian-Ping Lu Hamilton, Canada More articles by this author , and Jehonathan H. PinthusJehonathan H. Pinthus Hamilton, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.190AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Several recent studies have documented that lower levels of adiponectin, a hormone secreted from adipocytes only, are associated with increased incidence and aggressiveness of renal cell carcinoma (RCC). We and others demonstrated that adiponectin induced tumor suppression is mediated through its receptor AdipoR1 and downstream via AMPK. AMPK itself is a key regulator of mTOR and accumulating data suggests that its under-activation can result from various genetic defects seen in familial sub-types of RCC (BHD, TS) as well as by hypo-adiponectinemia in sporadic RCC. The endoplasmic reticulum (ER) protein ERp46, a member of the thioredoxin family of ER proteins, has been suggested as an inhibitor of this pathway. We examined this hypothesis using in-vitro and in-vivo models of RCC. METHODS The human RCC CRL-1932 and the murine RCC CCL-142 cells served as models. For co-immune precipitation studies an antibody against AdipoR1 covalently bound to magnetic Dynabeads was used for immune precipitation, while an antibody against ERp46 was used for detection. Gain and loss of function experiments were done following specific ERp46 ShRNA knock down and ERp46 over-expression respectively. The in vivo growth of different ERp46-manipulated subclones was investigated. RESULTS Transient knockdown of ERp46 leads to an increase in phosphorylation of AMPKα in CRL-1932 and CCL-142 cells compared to scrambled control, as determined by Western blot analysis. The tumor weight and volume from mice injected with renal cancer cells stably expressing shRNA specific for ERp46 (ERp46 KD; 80% knockdown of ERp46 protein expression) were significantly lower than from mice injected with cells transfected with scrambled control shRNA. Likewise, tumor weight and volume from mice injected with ERp46-overexpressing RCC cells (ERp46+; 4-fold increase in ERp46 protein expression) were significantly higher than from mice injected with empty vector (EV) control-transfected cells. CONCLUSIONS ERp46 is a negative modulator of AdipoR1 activity in RCC. Upon binding to AdipoR1, ERp46 inhibits the activation of AMPK and thus promotes tumorigenesis. Further characterization of this novel pathway may lead to better understanding of RCC biology and to the development of novel targeted therapies. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e58 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Wilhelmina C. Duivenvoorden Hamilton, Canada More articles by this author Jian-Ping Lu Hamilton, Canada More articles by this author Jehonathan H. Pinthus Hamilton, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...