Hippo pathway monomerizes STAT3 to regulate prostate cancer growth.

Prostate cancer ranks among the most commonly diagnosed malignancies for men and has become a non-negligible threat for public health. Interplay between inflammatory factors and cancer cells renders inflammatory tissue environment as a predisposing condition for cancer development. The Hippo pathway is a conserved signaling pathway across multiple species during evolution that regulates tissue homeostasis and organ development. Nevertheless, whether Hippo pathway regulates cancer-related inflammatory factors remains elusive. Here, we show that high cell density-mediated activation of the Hippo pathway blunts STAT3 activity in prostate cancer cells. Hippo pathway component MST2 kinase phosphorylates STAT3 at T622, which is located in the SH2 domain of STAT3. This phosphorylation blocks the SH2 domain in one STAT3 molecule to bind with the phosphorylated Y705 site in another STAT3 molecule, which further counteracts IL6-induced STAT3 dimerization and activation. Expression of a nonphosphorylatable STAT3 T622A mutant enhances STAT3 activity and IL6 expression at high cell density and promotes tumor growth in a mice xenograft model. Our findings demonstrate that STAT3 is a novel phosphorylation substrate for MST2 and thereby highlight a regulatory cascade underlying the crosstalk between inflammation and the Hippo pathway in prostate cancer cells.

Metabolic changes detected by ex vivo high resolution 1H NMR spectroscopy in the striatum of 6-OHDA-induced Parkinson's rat.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons; however, its crucial mechanism of the metabolic changes of neurotransmitters remains ambiguous. The pathological mechanism of PD might involve cerebral metabolism perturbations. In this study, ex vivo proton nuclear magnetic resonance ((1)H NMR) was used to determine the level changes of 13 metabolites in the bilateral striatum of 6-hydroxydopamine (6-OHDA)-induced PD rats. The results showed that, in the right striatum of 6-OHDA-induced PD rats, increased levels of glutamate (Glu) and γ-aminobutyric acid (GABA) concomitantly with decreased level of glutamine (Gln) were observed compared to the control. Whereas, in the left striatum of 6-OHDA-induced PD rats, increased level of Glu with decreased level of GABA and unchanged Gln were observed. Other cerebral metabolites including lactate, alanine, creatine, succinate, taurine, and glycine were also found to have some perturbations. The observed metabolic changes for Glu, Gln, and GABA are mostly likely the result of a shift in the steady-state equilibrium of the Gln-Glu-GABA metabolic cycle between astrocytes and neurons. The altered Gln and GABA levels are most likely as a strategy to protect neurons from Glu excitotoxic injury after striatal dopamine depletion. Changes in energy metabolism and tricarboxylic acid cycle might be involved in the pathogenesis of PD.