Following an investigation by the University of the Ryukyus, which revealed that figures that appeared within this paper had also been used in other papers without appropriate attribution or explanation (a pattern repeated over a number of publications in different journals), the Editorial Board of the Biochemical Journal retract this paper. The last author, Naoki Mori, takes full responsibility for the misrepresentation of data in this paper.

Increased glucose uptake and metabolism is a universal characteristic of advanced solid cancers. There are two well-established mechanisms underlying the reprogramming of tumor metabolism. First, intratumoral hypoxia induces the activity of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) by inhibiting the O2-dependent prolyl and asparaginyl hydroxylases that inhibit HIF-1α stability and transactivation, respectively. Second, genetic alterations increase the activity of HIF-1, thereby increasing the expression of glucose transporters (GLUT1, GLUT3), glycolytic enzymes (ALDOA, ENO1, HK2, LDHA, PKM2), pH regulators (CAR9, NHE1, MCT4), and proteins that inhibit mitochondrial metabolism (BNIP3, PDK1). Metabolites, such as the glycolytic end-product lactate, also induce HIF-1 activity, thereby providing a signal to further increase glycolytic metabolism. Recently, we have identified a novel feed-forward mechanism by which glycolytic enzyme expression leads to increased HIF-1 transcriptional activity. Pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM2 gene. PKM2, but not PKM1, alters glucose metabolism in cancer cells and contributes to tumorigenesis by mechanisms that are not explained by its known biochemical activity. We show that PKM2 gene transcription is activated by HIF-1. PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, whereas PKM1 fails to regulate HIF-1 activity. Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O2 consumption in cancer cells. Thus, PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells (1). HIF-1 also plays critical roles in breast cancer metastasis. HIF-1 controls metastatic niche formation by activating transcription of genes encoding lysyl oxidase (LOX) and LOX-like proteins 2 and 4, which remodel collagen in the lungs, thereby recruiting bone marrow-derived cells that establish a microenvironment suitable for colonization by breast cancer cells (2). HIF-1 also promotes the extravasation of circulating breast cancer cells in the lungs by activating transcription of the genes encoding L1CAM, which encodes a cell adhesion molecule that promotes the interaction of breast cancer cells with vascular endothelial cells (ECs), and angiopoietin-like 4, which encodes a secreted factor that inhibits EC-EC interaction (3). Inhibition of HIF-1 activity by genetic or pharmacologic strategies dramatically inhibits the metastasis of breast cancer cells to the lungs in orthotopic mouse models (2, 3). (1) Luo W. et al. Cell 2011;145:732. (2) Wong CC et al. Proc Natl Acad Sci USA 2011 Sept 12. doi:10.1073/pnas.1113483108. (3) Zhang H. et al. Oncogene 2011 Aug 22. doi: 10.1038/onc.2011.365. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr MS3-2.