Editors' ChoiceCancer

Acetylation for Autophagy

Sci. Signal.  28 Jun 2011:
Vol. 4, Issue 179, pp. ec182
DOI: 10.1126/scisignal.4179ec182

Cancer cells take up glucose at higher rates than normal cells but metabolize it through glycolysis rather than oxidative phosphorylation, a phenomenon known as the Warburg Effect. This metabolic switch occurs because the abundance of the M2 isoform of pyruvate kinase (PKM2) is higher in cancer cells than in normal cells. While performing a mass spectrometry analysis of acetylated proteins in a prostate cancer cell line, Lv et al. (see also Macintyre and Rathmell) found that PKM2 was acetylated, mainly at Lys305. Catalytic activity of PKM2 was moderately decreased by an Arg substitution at position 305 (K305R, a mutation that prevents acetylation) and more markedly decreased by a Gln substitution at position 305 (K305Q, a mutation that mimics acetylation). Incubation of 293T cells with high glucose concentrations elicited increased acetylation of PKM2 at Lys305, decreased PKM2 abundance, and increased association of PKM2 with the acetyltransferase PCAF. Ectopic expression of PCAF increased acetylation of PKM2 at Lys305 and decreased PKM2 activity. Glucose decreased the abundance of PKM2 by promoting its degradation through chaperone-mediated autophagy. Acetylation of PKM2 enhanced its interaction with the lysosomal protein HSC70 and increased the lysosomal uptake of PKM2. H1299 cells lacking endogenous PKM2 that were reconstituted with the K305Q PKM2 mutant showed higher amounts of glycolytic metabolites and proliferated faster than those reconstituted with wild-type PKM2, and nude mice injected with cells expressing the K305Q PKM2 mutant form developed larger tumors. The authors propose that glucose-induced acetylation of PKM2, which inhibits its activity and triggers its autophagic degradation, promotes increased amounts of glycolytic intermediates that enable tumor growth and cell proliferation.

L. Lv, D. Li, D. Zhao, R. Lin, Y. Chu, H. Zhang, Z. Zha, Y. Liu, Z. Li, Y. Xu, G. Wang, Y. Huang, Y. Xiong, K.-L. Guan, Q.-Y. Lei, Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol. Cell 42, 719–730 (2011). [PubMed]

A. N. Macintyre, J. C. Rathmell, PKM2 and the tricky balance of growth and energy in cancer. Mol. Cell 42, 713–714 (2011). [PubMed]