Shmt2: A Stat3 Signaling New Player in Prostate Cancer Energy Metabolism
Ilaria Marrocco,
Fabio Altieri,
Elisabetta Rubini,
Giuliano Paglia,
Silvia Chichiarelli,
Flavia Giamogante,
Alberto Macone,
Giacomo Perugia,
Fabio Massimo Magliocca,
Aymone Gurtner,
Bruno Maras,
Rino Ragno,
Alexandros Patsilinakos,
Roberto Manganaro,
Margherita Eufemi
Affiliations
Ilaria Marrocco
Department of Biochemical Sciences “A. Rossi Fanelli” and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy
Fabio Altieri
Department of Biochemical Sciences “A. Rossi Fanelli” and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy
Elisabetta Rubini
Department of Biochemical Sciences “A. Rossi Fanelli” and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy
Giuliano Paglia
Department of Biochemical Sciences “A. Rossi Fanelli” and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy
Silvia Chichiarelli
Department of Biochemical Sciences “A. Rossi Fanelli” and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy
Flavia Giamogante
Department of Biochemical Sciences “A. Rossi Fanelli” and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy
Alberto Macone
Department of Biochemical Sciences “A. Rossi Fanelli” and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy
Giacomo Perugia
Department of Maternal Child and Urologic Sciences, Sapienza University, V.le Dell’Università 33, 00185 Rome, Italy
Fabio Massimo Magliocca
Department of Radiological, Oncological and Pathological Sciences, Sapienza University, V.le del Policlinico 155, 00161 Rome, Italy
Aymone Gurtner
Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute; via Elio Chianesi 53, 00144 Rome, Italy
Bruno Maras
Department of Biochemical Sciences “A. Rossi Fanelli” and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy
Rino Ragno
Rome Center for Molecular Design, Sapienza University, P.le Aldo Moro 5, 00185 Rome, Italy
Alexandros Patsilinakos
Rome Center for Molecular Design, Sapienza University, P.le Aldo Moro 5, 00185 Rome, Italy
Roberto Manganaro
Alchemical Dynamics s.r.l., 00125 Rome, Italy
Margherita Eufemi
Department of Biochemical Sciences “A. Rossi Fanelli” and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy
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.
