Two major metabolic systems are usually used to generate ATP: oxidative phosphorylation (OXPHOS) in the mitochondria and glycolysis. Most types of cells employ OXPHOS for ATP production during normoxia but then shift energy production from OXPHOS to glycolysis when exposed to hypoxia. Hypoxia-inducible factor-1 (HIF-1) is the master transcription factor regulating this metabolic shift. On the other hand, macrophages are unique in making use of glycolysis for ATP generation constitutively even during normoxia. We recently proposed that in macrophages, Mint3/APBA3 inhibits factor inhibiting HIF-1 (FIH-1) during normoxia, which in turn releases the suppression of HIF-1 activity by FIH-1. To demonstrate the physiological function of APBA3 in macrophages, we established Apba3 ؊/؊ mice. The mutant mice presented no apparent gross phenotype but exhibited significant resistance against LPS-induced septic shock. The level of ATP in macrophages obtained from the mutant mice was reduced to 60% of the level observed in wild type cells, which in turn led to reduced ATP-dependent activities such as glycolysis, cytokine production, and motility. We also generated mutant mice with the Apba3 gene deleted specifically from cells of the myeloid lineage and confirmed that LPS-induced septic shock is mitigated significantly. Thus, we show cell type-specific regulation of energy production by APBA3 in macrophages using genetically manipulated mice. The specific function of APBA3 in macrophages might allow us to develop therapeutics to regulate aberrant macrophage function during infection and diseases.Macrophages are major players in the innate immune system, which regulates early inflammatory responses against invading pathogens (1, 2). Macrophages also play pivotal roles in tissue homeostasis by communicating with cells in wounds.During inflammation, macrophages produce cytokines, growth factors, and reactive oxygen molecules, thereby contributing to the pathology of various disease states (1-3). Inflammation often creates hypoxic conditions that are hazardous for cells. Exposure of cells to hypoxia leads to the induction of a survival program that either allows the cells to escape from such an environment or to adapt to it. In contrast, macrophages have to move into the inflamed tissue actively, despite the toxicity of hypoxia. For this purpose, macrophages employ an oxygen-independent energy production system unlike most other cells.Although most cells produce ATP via oxidative phosphorylation (OXPHOS), 2 this process becomes inefficient when the oxygen supply is limited (4). To adapt to hypoxia, cells shift energy production from OXPHOS to glycolysis (anaerobic glycolysis), an oxygen-independent means of ATP production. Macrophages, however, are unique in that they make use of glycolysis for ATP production constitutively even during normoxia (aerobic glycolysis), and OXPHOS activity in macrophages is low (5, 6). The glucose analog 2-deoxyglucose (2-DG) inhibits glycolysis and ATP production in macrophages, whereas the OXPHOS inh...

Cancer metastasis is intricately orchestrated by both cancer and normal cells, such as endothelial cells and macrophages. Monocytes/macrophages, which are often co-opted by cancer cells and promote tumor malignancy, acquire more than half of their energy from glycolysis even during normoxic conditions. This glycolytic activity is maintained during normoxia by the functions of hypoxia inducible factor 1 (HIF-1) and its activator APBA3. The mechanism by which APBA3 inhibition partially suppresses macrophage function and affects cancer metastasis is of interest in view of avoidance of the adverse effects of complete suppression of macrophage function during therapy. Here, we report that APBA3-deficient mice show reduced metastasis, with no apparent effect on primary tumor growth. APBA3 deficiency in inflammatory monocytes, which strongly express the chemokine receptor CCR2 and are recruited toward chemokine CCL2 from metastatic sites, hampers glycolysis-dependent chemotaxis of cells toward metastatic sites and inhibits VEGFA expression, similar to the effects observed with HIF-1 deficiency. Host APBA3 induces VEGFA-mediated E-selectin expression in the endothelial cells of target organs, thereby promoting extravasation of cancer cells and micrometastasis formation. Administration of E-selectin-neutralizing antibody also abolished host APBA3-mediated metastatic formation. Thus, targeting APBA3 is useful for controlling metastatic niche formation by inflammatory monocytes.APBA3/Mint3 | macrophage | metastasis C ancer metastasis comprises multiple processes of neoplastic progression, termed the "invasion-metastasis cascade" (1, 2). Thousands of circulating tumor cells (CTCs) can be released from invasive primary tumors; however, most patients develop only a few metastases, suggesting that metastatic initiation processes (such as extravasation and colonization at distant organs) are quite inefficient but key for controlling metastatic cancer diseases. Unlike at primary sites, single or small groups of disseminated CTCs encounter large numbers of normal cells in their new environments, which determines their survival and metastatic efficiency, as shown by studies with genetically engineered mouse models (3-5).Macrophages are myeloid cells that are co-opted essentially to foster tumor progression and metastasis. The functions of tumorassociated macrophages include angiogenesis, suppression of antitumor immune responses, chemoresistance, and metastasis; these are considered novel targets for cancer therapy (6-10). Monocytes (i.e., macrophage precursors) are characterized by the surface molecules CD11b and CD115, and comprise at least two subsets: Gr-1 + (Ly-6C high )CCR2 + CX3CR1 low inflammatory monocytes (IMs) and Gr-1 low (Ly-6C low )CCR2 low CX3CR1 high resident monocytes (RMs) (11). Their recruitment from the bone marrow (BM) to peripheral tissues is mediated mainly by chemokine-chemokine receptor complexes such as the CCL2/CCR2 system (12, 13). Even in metastatic cascades, the CCL2-CCR2 axis is a key pathway for IM ...

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