mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

Abstract

Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation1,2. Here we show that mTORC1 regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. Through the use of integrative metabolomics in a mouse model3 and human biopsies4 of prostate cancer, we identified alterations in tumours impacting on the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation was validated in murine and human cancer specimens. AMD1 was upregulated in prostate cancer specimens with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus5 exhibited a predominant decrease in AMD1 immunoreactivity that was associated to a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

Protein-Protein Interaction Network Analysis and Identification of Key Players in nor-NOHA and NOHA Mediated Pathways for Treatment of Cancer through Arginase Inhibition: Insights from Systems Biology

“…SOD1 however has been only recently been proposed as a novel target for cancer therapy [24] and its role in cancer is also being revealed [25]. More recently being elucidated is the role of AMD1 in cancer which has been found to be upregulated in human prostate cancer [26]. NOS2 is another one which has been recently being seen as a emerging target for cancer treatment [27][28].…”

Adding Polyamine Metabolism to the mTORC1 Toolkit in Cell Growth and Cancer

“…However, the larger picture of mTORC1-mediated metabolic regulation and how it drives cellular oncogenesis is still an active and attractive area of research. In a recent issue of Nature , Zabala-Letona et al (2017) demonstrate that in addition to the previously reported roles in driving anabolic processes, mTORC1 regulates polyamine flux to promote cell proliferation and growth in prostate cancer.…”

“…Reporting recently in Nature , Zabala-Letona et al (2017) show that mTORC1 regulates an additional branch of metabolism in the cell—polyamine synthesis—that is important for prostate cancer tumorigenicity. …”

“…Interestingly, Zabala-Letona et al (2017) show that polyamine metabolism is the main metabolic pathway altered in PTEN loss-driven prostate cancers in both animal models and human biopsies. The authors set out to explore how polyamine synthesis is altered in these cancers and determined it to be dependent on mTORC1 activation.…”

“…These results add a new layer of metabolic regulation by mTORC1 to support cellular growth and proliferation, as well as reaffirm the role of mTORC1 as a major regulator of cellular homeostasis (Figure 1). Though Zabala-Letona et al (2017) elegantly show that the mTORC1 signaling network regulates AMD1 phosphorylation, precisely how it happens remains unclear. Therefore, determining which mTORC1-regulated kinase is the missing link between mTORC1 activity and AMD1 regulation remains an important open question before the complete understanding of this mTORC1 regulatory network is achieved.…”