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

Department of Biochemical Sciences “A. Rossi Fanelli” and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy

Department of Maternal Child and Urologic Sciences, Sapienza University, V.le Dell’Università 33, 00185 Rome, Italy

Department of Radiological, Oncological and Pathological Sciences, Sapienza University, V.le del Policlinico 155, 00161 Rome, Italy

⁴

Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute; via Elio Chianesi 53, 00144 Rome, Italy

⁵

Rome Center for Molecular Design, Sapienza University, P.le Aldo Moro 5, 00185 Rome, Italy

⁶

Alchemical Dynamics s.r.l., 00125 Rome, Italy

Author to whom correspondence should be addressed.

^†

Current Affiliation: Department of Biological Regulation, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel.

Cells 2019, 8(9), 1048; https://doi.org/10.3390/cells8091048

Received: 25 July 2019 / Revised: 29 August 2019 / Accepted: 6 September 2019 / Published: 6 September 2019

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Prostate Cancer)

View Full-Text Download PDF

Browse Figures

Citation Export

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. View Full-Text

Keywords: STAT3; SHMT2; prostate cancer; signaling transduction; Warburg effect; cell metabolism

▼ Show Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Share and Cite

MDPI and ACS Style

Marrocco, I.; Altieri, F.; Rubini, E.; Paglia, G.; Chichiarelli, S.; Giamogante, F.; Macone, A.; Perugia, G.; Magliocca, F.M.; Gurtner, A.; Maras, B.; Ragno, R.; Patsilinakos, A.; Manganaro, R.; Eufemi, M. Shmt2: A Stat3 Signaling New Player in Prostate Cancer Energy Metabolism. Cells 2019, 8, 1048. https://doi.org/10.3390/cells8091048

AMA Style

Marrocco I, Altieri F, Rubini E, Paglia G, Chichiarelli S, Giamogante F, Macone A, Perugia G, Magliocca FM, Gurtner A, Maras B, Ragno R, Patsilinakos A, Manganaro R, Eufemi M. Shmt2: A Stat3 Signaling New Player in Prostate Cancer Energy Metabolism. Cells. 2019; 8(9):1048. https://doi.org/10.3390/cells8091048

Chicago/Turabian Style

Marrocco, Ilaria, Fabio Altieri, Elisabetta Rubini, Giuliano Paglia, Silvia Chichiarelli, Flavia Giamogante, Alberto Macone, Giacomo Perugia, Fabio M. Magliocca, Aymone Gurtner, Bruno Maras, Rino Ragno, Alexandros Patsilinakos, Roberto Manganaro, and Margherita Eufemi. 2019. "Shmt2: A Stat3 Signaling New Player in Prostate Cancer Energy Metabolism" Cells 8, no. 9: 1048. https://doi.org/10.3390/cells8091048

Find Other Styles

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Metrics

Abstract views Pdf views Html views

Article Menu

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

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Article Access Map by Country/Region

Further Information

Guidelines

MDPI Initiatives

Follow MDPI