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

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.

β-Hexachlorocyclohexane: A Small Molecule with a Big Impact on Human Cellular Biochemistry

“…Reduced (GSH) and oxidized (GSSG) glutathione were measured by HPLC-UV according to Marrocco et al [ 10 ]. Briefly, LNCaP and HepG2 cell pellets (1 × 10 6 cells) were suspended in 10% ice-cold TCA and centrifuged for 15 min at 9000× g .…”

“…Reduced (GSH) and oxidized (GSSG) glutathione were measured by HPLC-UV according to Marrocco et al [10]. Briefly, LNCaP and HepG2 cell pellets (1 × 10 6 cells) were suspended in 10% ice-cold TCA and centrifuged for 15 min at 9000× g. The supernatant was collected and GSH and GSSG were measured by HPLC using a poroshell 120 EC-C18 column (3 × 150 mm, 2.7 µm) with UV detection at 215 nm.…”

Cell-Type Specific Metabolic Response of Cancer Cells to Curcumin

“…An important aspect of the pro-proliferative effect of SHMT2 is generating methyl-tetrahydrofolate, an essential intermediate for purine biosynthesis, in the process of converting serine into glycine [15]. A very recent report showed that SHMT2 promoter contains a strong STAT3 binding site in its promoter, but the physical binding of STAT3 for this region was not shown [16]. STAT3 activity is closely related to PKM2 protein kinase activity, as PKM2 can also use the PEP as the phosphate donor for transferring the phosphate group on STAT3 (P-Y705) [17].…”

Increased Expression of SHMT2 Is Associated With Poor Prognosis and Advanced Pathological Grade in Oral Squamous Cell Carcinoma

“…In contrast, OSCC patients with a lower SHMT2 expression possess higher overall survival rates and better prognoses, similar with the results in breast cancer. These findings suggested that SHMT2, the high expression of which can slow down the process of glycolysis and augment the ratio of lactate and pyruvate, plays a vital role in the transition of PKM2, resulting in the glycolytic metabolic shift ( 10 , 15 , 34 ). It is known that one of the OSCC microenvironment features is hypoxia and that normal epithelial cells cannot adjust at poor oxygen pressure, so a high expression of SHMT2 may promote tumor cell survival for a long time in the OSCC microenvironment ( 9 ).…”

“…Furthermore, it has been reported that SHMT2 is highly expressed in glioma, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma ( 12 ), reflecting that SHMT2 is partly involved in the process of tumorigenicity ( 10 , 12 , 13 ). It has been suggested that SHMT2 is downstream of signal transducer and activator of transcription 3 (STAT3) and plays a key role in the conversion of prostate cancer to a more aggressive phenotype ( 14 , 15 ). However, it is not clear if SHMT2 is expressed in the OSCC microenvironment and whether SHMT2 is related to the prognosis of OSCC patients.…”