UDP-glucoseaccelerates SNAI1 mRNA decay and impairs lung cancer metastasis.

Doramapimod purchased from MCE.

UDP-glucose6-dehydrogenase (UGDH) is a key enzyme in the uronic acid pathway, and converts UDP-glucose to UDP-glucuronic acid.  Afteractivation of EGFR, UGDH is phosphorylated at tyrosine 473 in human lung cancer cells. Phosphorylated UGDH interacts with Hu antigen R and converts UDP-glucose to UDP-glucuronic acid, which attenuates the UDP-glucose-mediated inhibition of the association of HuR with SNAI1 mRNAand therefore enhances the stability of SNAI1 mRNA. Increase dproduction of SNAIL initiates the epithelial–mesenchyme transition, thus promoting the migration of tumor cells and lung cancer metastasis. Researchers’findings reveal a tumor-suppressive role of UDP-glucose in lung cancer metastasis and uncover a mechanism by which UGDH promotes tumor metastasis by increasing the stability of SNAI1 mRNA.

IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain.

KIRA6 purchased from MCE.

Researchers found that induciblebiosynthesis of prostaglandins, including the pro-algesic mediatorprostaglandin E2 (PGE₂), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivatedthe human PTGS2 and PTGES genes to enableoptimal PGE₂ production. Mice that lack IRE1α-XBP1 in leukocytes, orthat were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE₂-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.

BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis.

Researchers show thatlong-term supplementation with the antioxidants N-acetylcysteine and vitaminE promotes KRAS-driven lung cancer metastasis. The antioxidants stimulatemetastasis by reducing levels of free heme and stabilizing the transcriptionfactor BACH1. BACH1 activates transcription of Hexokinase 2 and Gapdh andincreases glucose uptake, glycolysis rates, and lactate secretion, therebystimulating glycolysis-dependent metastasis of mouse and human lung cancercells. Targeting BACH1 normalized glycolysis and prevented antioxidant-inducedmetastasis, while increasing endogenous BACH1 expression stimulated glycolysisand promoted metastasis, also in the absence of antioxidants. They conclude that BACH1 stimulates glycolysis-dependent lung cancer metastasis and that BACH1 is activated under conditions of reduced oxidative stress.