Metabolic alterations in prostate cancer pathogenesis

  1. ARRUABARRENA ARISTORENA, AMAIA
Supervised by:
  1. Arkaitz Carracedo Pérez Director

Defence university: Universidad del País Vasco - Euskal Herriko Unibertsitatea

Fecha de defensa: 16 September 2016

Committee:
  1. Ana María Zubiaga Elordieta Chair
  2. Guillermo Velasco Díez Secretary
  3. Raul V. Duran Díaz Committee member
Department:
  1. Bioquímica y Biología Molecular

Type: Thesis

Teseo: 120903 DIALNET lock_openADDI editor

Abstract

Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs thatsustain cell growth, proliferation and promote cancer initiation and progression. In this thesis workwe describe a novel molecular mechanism by which mTORC1 regulates polyamine dynamics, ametabolic route that is essential for oncogenicity. Through the integrative metabolomics analysisof a mouse model and human biopsies of prostate cancer, we identified alterations in tumorsimpacting on the production of decarboxylated S-Adenosylmethionine (dcSAM) and polyaminesynthesis. Mechanistically, we demonstrate that this metabolic rewiring stems from mTORC1-mediated post-transcriptional control of S-Adenosylmethionine decarboxylase 1 (AMD1). Thisnovel molecular regulation was pharmacologically validated in samples from murine pre-clinicaland human clinical trials with Everolimus. Importantly, we demonstrate that manipulation of AMD1levels and activity dictates prostate cancer oncogenicity. The results in this thesis providefundamental information about the complex regulatory landscape controlled by mTORC1 tointegrate and translate growth signals into an oncogenic metabolic program.