Editors' ChoiceCancer

The Sugar-Cancer Connection in 3D

Science Signaling  28 Jan 2014:
Vol. 7, Issue 310, pp. ec29
DOI: 10.1126/scisignal.2005117

Increased sugar metabolism through glycolysis is associated with cancer and may result from the transformed cell’s increased metabolic demand. Cancer progression typically involves the transformation of a nonmalignant phenotype to a malignant one. Using a three-dimensional culture system (3D lrECM), Onodera et al. found that increased glycolysis itself caused this switch from a nonmalignant to a malignant phenotype. Malignant T4-2 HMT-3522 breast cancer cells grown in 3D lrECM exhibited disorganized morphology, whereas nonmalignant S1 HMT-3522 cells formed polarized acinar structures. T4-2 cells had increased markers for glycolysis and increased expression of genes encoding glycolytic enzymes, such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH), compared with S1 cells. Among glucose transporters, GLUT3 was the most differentially increased at both the mRNA and protein level in T4-2 cells. Overexpression of GLUT3 in S1 cells increased glucose uptake and the activity of kinases Akt and MEK, which are associated with cell survival and proliferation, respectively, and induced a disorganized morphology, effects that were all prevented by glucose starvation or inhibiting glucose metabolism with 2-deoxy-D-glucose (2DG). Knockdown of GLUT3, glucose starvation, or treatment with 2DG induced polarity in T4-2 cells, such that the organization resembled that of the S1 cells. However, disrupting other metabolic pathways associated with oncogenesis [through inhibition or knockdown of mammalian target of rapamycin (mTOR) or hypoxia-inducible factors 1α and 2α (HIF1α/2α)] did not induce the formation of polarized clusters of T4-2 cells. Instead, using chemical inhibitors, RNA interference, and overexpression, Onodera et al. identified the enzyme GAPDH, the GTPase RAP1, and its guanine nucleotide exchange factor EPAC, as well as enzymes in the hexosamine biosynthesis pathway (HBP), as mediators of the glycolysis-induced loss of polarity in T4-2 cells. Microarrays from breast cancer patients showed that the expression of genes encoding HBP rate-limiting enzymes inversely correlated with prognosis. The findings show that increased sugar metabolism can initiate malignant changes in nonmalignant cells and that glycolysis mediated through HBP, GAPDH, EPAC, and RAP1 maintains malignant phenotypes in malignant cells.

Y. Onodera, J.-M. Nam, M. J. Bissell, Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. J. Clin. Invest. 124, 367–384 (2014). [PubMed]

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