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

被引：35

作者：

Marrocco, Ilaria ^{[1
,2
,8
]}

Altieri, F. Abio ^{[1
,2
]}

Rubini, Lisabetta ^{[1
,2
]}

Paglia, Giuliano ^{[1
,2
]}

Chichiarelli, Silvia ^{[1
,2
]}

Giamogante, Flavia ^{[1
,2
]}

Macone, Alberto ^{[1
,2
]}

Perugia, Giacomo ^{[3
]}

Magliocca, Fabio Massimo ^{[4
]}

Gurtner, Aymone ^{[5
]}

Maras, Bruno ^{[1
,2
]}

Ragno, Rino ^{[6
,7
]}

Patsilinakos, Lexandros ^{[6
,7
]}

Manganaro, Roberto ^{[7
]}

Eufemi, Margherita ^{[1
,2
]}

机构：

[1] Sapienza Univ, Dept Biochem Sci A Rossi Fanelli, Ple A Moro 5, I-00185 Rome, Italy

[2] Sapienza Univ, Ist Pasteur Fdn Cenci Bolognetti, Ple A Moro 5, I-00185 Rome, Italy

[3] Sapienza Univ, Dept Maternal Child & Urol Sci, Vle Univ 33, I-00185 Rome, Italy

[4] Sapienza Univ, Dept Radiol Oncol & Pathol Sci, Vle Policlin 155, I-00161 Rome, Italy

[5] Regina Elena Inst Canc Res, Dept Res Adv Diagnost & Technol Innovat, Translat Res Area, Via Elio Chianesi 53, I-00144 Rome, Italy

[6] Sapienza Univ, Rome Ctr Mol Design, Ple Aldo Moro 5, I-00185 Rome, Italy

[7] Alchem Dynam Srl, I-00125 Rome, Italy

[8] Weizmann Inst Sci, Dept Biol Regulat, 234 Herzl St, IL-7610001 Rehovot, Israel

来源：

CELLS | 2019年 / 8卷 / 09期

关键词：

STAT3; SHMT2; prostate cancer; signaling transduction; Warburg effect; cell metabolism; ONE-CARBON METABOLISM; SERINE CATABOLISM; MITOCHONDRIAL; SURVIVAL; GROWTH; PKM2;

D O I：

10.3390/cells8091048

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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-1 alpha/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.

引用

页数：20

共 52 条

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