Compared to normal cells, cancer cells strongly upregulate glucose uptake and glycolysis to give rise to increased yield of intermediate glycolytic metabolites and the end product pyruvate. Moreover, glycolysis is uncoupled from the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in cancer cells. Consequently, the majority of glycolysis-derived pyruvate is diverted to lactate fermentation and kept away from mitochondrial oxidative metabolism. This metabolic phenotype is known as the Warburg effect. While it has become widely accepted that the glycolytic intermediates provide essential anabolic support for cell proliferation and tumor growth, it remains largely elusive whether and how the Warburg metabolic phenotype may play a role in tumor progression. We hereby review the cause and consequence of the restrained oxidative metabolism, in particular in tumor metastasis. Cells change or lose their extracellular matrix during the metastatic process. Inadequate/inappropriate matrix attachment generates reactive oxygen species (ROS) and causes a specific type of cell death, termed anoikis, in normal cells. Although anoikis is a barrier to metastasis, cancer cells have often acquired elevated threshold for anoikis and hence heightened metastatic potential. As ROS are inherent byproducts of oxidative metabolism, forced stimulation of glucose oxidation in cancer cells raises oxidative stress and restores cells’ sensitivity to anoikis. Therefore, by limiting the pyruvate flux into mitochondrial oxidative metabolism, the Warburg effect enables cancer cells to avoid excess ROS generation from mitochondrial respiration and thus gain increased anoikis resistance and survival advantage for metastasis. Consistent with this notion, pro-metastatic transcription factors HIF and Snail attenuate oxidative metabolism, whereas tumor suppressor p53 and metastasis suppressor KISS1 promote mitochondrial oxidation. Collectively, these findings reveal mitochondrial oxidative metabolism as a critical suppressor of metastasis and justify metabolic therapies for potential prevention/intervention of tumor metastasis.

Summary The CD4+Foxp3+ lineage of regulatory T (Treg) cells plays a key role in controlling immune and autoimmune responses. Treg cells originate primarily during T cell differentiation in the thymus, but conversion of mature T lymphocytes to Foxp3-positivity can be elicited by several means, including activation in the presence of transforming growth factor (TGF)β in vitro. Retinoic Acid (RA), the ubiquitous morphogen that exerts a particular shepherding effect on the gut immune system, increases TGFβ–induced expression of Foxp3, an effect shown here to be mediated through RA receptor (RAR)α. Part of RA’s influence may be due to it’s ability to down-modulate the receptor for IL-6, a cytokine that inhibits Foxp3 expression, but this effect appeared to be of relatively minor importance. Rather, RA negatively affected a population of CD4+ cells with a CD44hi phenotype, akin to that of memory or effector cells, which inhibited the TGFβ-induced conversion of naïve CD4+ T cells. This “contra-conversion” activity was mediated, at least in part, through the synthesis of a set of cytokines (IL-4, IL-21, IFNγ), which in combination had a potent dampening effect on Foxp3 induction. RA, via RARα, elicited a coordinated shut-down of the whole program of cytokine expression in CD44hi cells. The in vivo relevance of this observation was established by transferring RA-sensitive OT-II T cells, which showed less effective conversion to Foxp3+ in RARα-deficient hosts. Thus, CD44hi T cells can actively restrain the induction of Foxp3, and this balance can be shifted or fine tuned by RA.

SUMMARY Autophagy is crucial for maintaining cell homeostasis. However, the precise mechanism underlying autophagy initiation remains to be defined. Here, we demonstrate that glutamine deprivation and hypoxia result in inhibition of mTOR-mediated acetyl-transferase ARD1 S228 phosphorylation, leading to ARD1-dependent phosphoglycerate kinase 1 (PGK1) K388 acetylation and subsequent PGK1-mediated Beclin1 S30 phosphorylation. This phosphorylation enhances ATG14L-associated class III phosphatidylinositol 3-kinase VPS34 activity by increasing the binding of phosphatidylinositol to VPS34. ARD1-dependent PGK1 acetylation and PGK1-mediated Beclin1 S30 phosphorylation are required for glutamine deprivation- and hypoxia-induced autophagy and brain tumorigenesis. Furthermore, PGK1 K388 acetylation levels correlate with Beclin1 S30 phosphorylation levels and poor prognosis in glioblastoma patients. Our study unearthed an important mechanism underlying cellular stress-induced autophagy initiation, in which the protein kinase activity of the metabolic enzyme PGK1 plays an instrumental role, and revealed the significance of the mutual regulation of autophagy and cell metabolism in maintaining cell homeostasis.