MP33-12 THE POTENTIAL ROLE OF CTLH COMPLEX IN THE PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP33)1 Sep 2021MP33-12 THE POTENTIAL ROLE OF CTLH COMPLEX IN THE PROSTATE CANCER Mario Scarpa, Marta De Menna, Eugenio Zoni, Sofia Karkampouna, and Marianna Kruithof-de Julio Mario ScarpaMario Scarpa More articles by this author , Marta De MennaMarta De Menna More articles by this author , Eugenio ZoniEugenio Zoni More articles by this author , Sofia KarkampounaSofia Karkampouna More articles by this author , and Marianna Kruithof-de JulioMarianna Kruithof-de Julio More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002042.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is the most frequent malignancy detected in men and the second leading cause of cancer-related male death in Europe. Current markers frequently fail in providing an effective patient stratification. Unfortunately, lethal cases receive new therapies only when they have failed local and hormonal treatment. This project is focused on the role, in PCa progression, of Ran Binding Protein 9 (RanBP9), a key component of the mammalian macromolecular complex CTLH E3-ubiquitin ligase. This complex is characterized by well conserved CTLH domain and in DU145 cell lines its ubiquitin ligase activity increases cell radiosensitivity. All these evidences suggest that the CTLH Complex, through RanBP9, is potentially involved in the PCa tumorigenesis. METHODS: To elucidate the biological mechanism and function of CTLH in the PCa, we performed in vitro analyses using prostate cancer cell lines as: PC3, LNCaP and C42B. To study the role of the CTLH complex in vivo we are using PDXs BM18 (androgen dependent), LAPC9 (androgen-independent) and GEMM for PCa: Nkx3.1CreERT2/+; Pten flox/flox; R26LSL-YFP (NP) and Nkx3.1CreERT2/+; Pten flox/flox; KRas LSLG12D/+; R26 LSL-YFP (NPK). In particular NP and NPK animals mimic different stages of PCa tumorigenesis. After tamoxifen treatment NP animals will develop high grade PIN lesions while the NPK animals will develop prostate adenocarcinoma with lung and liver metastasis. RESULTS: The levels of RanBP9 were measured on a TMA (Tissue Micro Array) of 201 High-Risk PCa patients. It revealed that higher levels of RanBP9 was associated with PSA progression. Also, in the TMA cells expressing NKX3.1 were low compare a higher number of cells expressing RanBP9. In the GEMM models NP and NPK, RanBP9 expression is higher in the more aggressive phenotype (NP primary vs NPK primary and metastasis). Interesting, the level of RanBP9 expression were particularly higher in NPK metastasis vs NPK primary. RanBP9 levels were measured in PDXs LAPC9 and BM18 in both intact and castrated setting. Interestingly, levels of RanBP9 in both PDXs model were affected by castration. Currently, to further explore the relationship between RanBP9 and the AR axis we are generating RanBP9-KD stable clones in PC3 (AR-) and LNCaP (AR+) cell lines. CONCLUSIONS: Our results suggested that RanBP9 expression is correlated with PCa progression. The modulation of the RanBP9 expression is probably regulated by the presence of testosterone due its downregulation following castration beyond the androgen-dependent or -independent profile of PCa. Source of Funding: KFS 4960-02-2020 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e611-e611 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mario Scarpa More articles by this author Marta De Menna More articles by this author Eugenio Zoni More articles by this author Sofia Karkampouna More articles by this author Marianna Kruithof-de Julio More articles by this author Expand All Advertisement Loading ...