Removing a Metabolic Roadblock

Science Signaling  30 Aug 2011:
Vol. 4, Issue 188, pp. ec240
DOI: 10.1126/scisignal.4188ec240

Although loss of attachment to the extracellular matrix (ECM) impairs metabolism and induces apoptosis in cultured epithelial cells, tumor cells are able to avoid death and overcome the metabolic impairments to survive detachment. When apoptosis is inhibited in detached nontransformed mammary epithelial (MCF-10A) cells, the cells show reduced ATP production and glucose uptake associated with decreased signaling through the PI3 kinase (PI3K)-Akt pathway. Expression of the receptor tyrosine kinase ErbB2 enables cells to survive ECM detachment by rescuing the reduced ATP and glucose uptake phenotypes. Grassian et al. report that ECM-detached cells showed decreased flux through the tricarboxylic acid (TCA) cycle, which was characterized by reduced activity of the key TCA cycle enzyme pyruvate dehydrogenase (PDH) and increased pyruvate secretion. Detachment also increased the abundance of the PDH inhibitor PDH kinase 4 (PDK4). ErbB2 suppressed the increase in PDK4 and partially rescued the TCA cycle phenotype by signaling through the ERK (extracellular signal–regulated kinase) pathway rather than through the PI3K-Akt pathway. Activating ERK signaling by epidermal growth factor (EGF) or insulin reduced PDK4 abundance in adherent cells and stimulated flux through the TCA cycle, with EGF being more potent. The TCA cycle not only generates ATP but also produces precursors of materials required for proliferation, such as lipids and amino acids. Accordingly, overexpression of PDK4 reduced de novo lipogenesis and proliferation in adherent cells. Moreover, the abundance of PDK4 transcripts correlated inversely with the proliferation rate of MCF-10A cells in 3D culture and was decreased in various tumors compared with tissue-of-origin controls in many published microarray data sets. Thus, one of the mechanisms by which tumor cells may overcome the metabolic consequences of ECM detachment and continue to proliferate is by stimulating flux through the TCA cycle.

A. R. Grassian, C. M. Metallo, J. L. Coloff, G. Stephanopoulos, J. S. Brugge, Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation. Genes Dev. 25, 1716–1733 (2011). [Abstract] [Full Text]