Shmt2: A Stat3 Signaling New Player in Prostate Cancer Energy Metabolism.

Marrocco Marrocco,Altieri Altieri,Eufemi Eufemi,Perugia Perugia,Magliocca Magliocca,Ragno Ragno,Giamogante Giamogante,Gurtner Gurtner,Macone Macone,Patsilinakos Patsilinakos,Maras Maras,Rubini Rubini,Paglia Paglia,Manganaro Manganaro,Chichiarelli Chichiarelli

doi:10.3390/cells8091048

Marrocco Marrocco, Altieri Altieri + Show 13 more

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https://doi.org/10.3390/cells8091048

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Abstract

Prostate cancer (PCa) is a multifactorial disease characterized by the aberrant activity of different regulatory pathways. STAT3 protein mediates some of these pathways and its activation is implicated in the modulation of several metabolic enzymes. A bioinformatic analysis indicated a STAT3 binding site in the upstream region of SHMT2 gene. We demonstrated that in LNCaP, PCa cells’ SHMT2 expression is upregulated by the JAK2/STAT3 canonical pathway upon IL-6 stimulation. Activation of SHTM2 leads to a decrease in serine levels, pushing PKM2 towards the nuclear compartment where it can activate STAT3 in a non-canonical fashion that in turn promotes a transient shift toward anaerobic metabolism. These results were also confirmed on FFPE prostate tissue sections at different Gleason scores. STAT3/SHMT2/PKM2 loop in LNCaP cells can modulate a metabolic shift in response to inflammation at early stages of cancer progression, whereas a non-canonical STAT3 activation involving the STAT3/HIF-1α/PKM2 loop is responsible for the maintenance of Warburg effect distinctive of more aggressive PCa cells. Chronic inflammation might thus prime the transition of PCa cells towards more advanced stages, and SHMT2 could represent a missing factor to further understand the molecular mechanisms responsible for the transition of prostate cancer towards a more aggressive phenotype.

Highlights

Prostate cancer (PCa) is a biologically heterogeneous disease, with great differences in its clinical and histological features
Results obtained by RT-PCR (Figure 6D) are consistent with those highlighted by Western blot analysis and, differently from LNCaP cells, SHMT2 expression in DU145 cells did not seem to be under IL6/JAK2/STAT3 pathway control
STAT3 is an oncoprotein involved in multiple regulatory pathways and could represent a crossroad between signal transduction and metabolism control

Summary

Introduction

Prostate cancer (PCa) is a biologically heterogeneous disease, with great differences in its clinical and histological features. The establishment of the Warburg effect drives tumor cells to high glucose consumption, a reduction in cellular respiration, and an increased synthesis of one-carbon units [3] for the biosynthesis of nucleotides, proteins, and lipids, together with glutathione [4]. As result of this metabolic shift, PCa cells survive, even in the presence of a significantly increased demand of precursors that occurs during uncontrolled proliferation. The requirement of higher energy levels is supplied by a rise in oxidative phosphorylation that, in turn, could result in an increased and harmful ROS production [5]

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