Normal cells produce adenosine 5′-triphosphate (ATP) mainly through mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is available. Most cancer cells, on the other hand, are known to produce energy predominantly through accelerated glycolysis, followed by lactic acid fermentation even under normoxic conditions. This metabolic phenomenon, known as aerobic glycolysis or the Warburg effect, is less efficient compared with OXPHOS, from the viewpoint of the amount of ATP produced from one molecule of glucose. However, it and its accompanying pathway, the pentose phosphate pathway (PPP), have been reported to provide advantages for cancer cells by producing various metabolites essential for proliferation, malignant progression, and chemo/radioresistance. Here, focusing on a master transcriptional regulator of adaptive responses to hypoxia, the hypoxia-inducible factor 1 (HIF-1), we review the accumulated knowledge on the molecular basis and functions of the Warburg effect and its accompanying pathways. In addition, we summarize our own findings revealing that a novel HIF-1-activating factor enhances the antioxidant capacity and resultant radioresistance of cancer cells though reprogramming of the glucose metabolic pathway.

Hypoxia‐inducible factor 1 (HIF‐1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF‐1 activity have been implicated in the pathogenesis of various diseases including malignant tumors and, thus, elucidating the molecular mechanisms underlying the activation of HIF‐1 is eagerly desired for the development of novel anti‐cancer strategies. The importance of oxygen‐dependent and ubiquitin‐mediated proteolysis of the regulatory subunit of HIF‐1 (HIF‐1α) was first reported in 1997. Since then, accumulating evidence has shown that HIF‐1α may become stable and active even under normoxic conditions; for example, when disease‐associated genetic and functional alterations in some genes trigger the aberrant activation of HIF‐1 regardless of oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF‐1 activity from conventional oxygen‐ and proteolysis‐dependent mechanisms to up‐to‐the‐minute information on cancer‐associated genetic and functional alteration‐mediated mechanisms.

Purpose The success of hematopoietic stem cell transplantation (HSCT) depends on donor cell homing to the bone marrow (BM). However, there is no reliable method of noninvasively monitoring the kinetics and distribution of transferred cells. Using Zirconium-89 (89Zr)-oxine cell labeling combined with positron emission tomography (PET) imaging, we sought to visualize and quantify donor cell homing in a mouse BM transplantation model. Experimental Design The effect of 89Zr-oxine labeling on BM cell viability and differentiation was evaluated in vitro. 89Zr-labeled BM cells (2×107 cells, 16.6 kBq/106 cells) were transferred intravenously and serial microPET images were obtained (n=5). The effect of a CXCR4 inhibitor, plerixafor, (5 mg/kg) and granulocyte-colony stimulation factor (G-CSF, 2.5 μg) on BM homing and mobilization were examined (n=4). Engraftment of the transferred 89Zr-labeled cells was evaluated (n=3). Results 89Zr-oxine-labeled BM cells showed delayed proliferation, but differentiated normally. Transferred BM cells rapidly migrated to the BM, spleen, and liver (n=5). Approximately 36% of donor cells homed to the BM within 4 h, irrespective of prior BM ablation. Inhibition of CXCR4 by plerixafor alone or with G-CSF significantly blocked the BM homing (p<0.0001, vs non-treated, at 2 h), confirming a crucial role of the CXCR4-CXCL12 system. Mobilization of approximately 0.64% of pre-transplanted BM cells induced a 3.8-fold increase of circulating BM cells. 89Zr-labeled donor cells engrafted as well as non-labeled cells. Conclusions 89Zr-oxine PET imaging reveals rapid BM homing of transferred BM cells without impairment of their stem cell functions, and thus, could provide useful information for optimizing HSCT.