Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses (Science, 2011, 334:1278-1283)

報告日期: 2012/11/23
報告時間: 16:00/16:50
報告學生: 楊理行
講評老師: 蔡少正
附件下載: 下載[1248-1348734671-1.pdf] 

 

Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses

 

Anastasiou D., Poulogiannis G., Asara J. M., Boxer M. B., Jiang J. K., Shen M., Bellinger G., Sasaki A. T., Locasale J. W., Auld D.S., Thomas C.J., Vander Heiden M. G., and Cantley L. C.

Science 334, 1278-1283, December 2, 2011

 

Speaker: Li-Xing Yang                               Date: 2012.11.23                        Commentator: Shaw-Jeng Tsai, Ph.D.

Abstract:

    The intracellular concentration of reactive oxygen species (ROS) plays important roles in cell proliferation and survival regulation. Transiently increased ROS concentration can enhance cell proliferation, but high concentration of ROS can also cause cellular components damage and lead to decreased cell viability (1). Cancer cells are commonly challenged in dealing with the oxidative stresses which are caused by numerous tumorigenic conditions. The detoxification of ROS primarily depends on the availability of reduced glutathione (GSH) which maintained by NADPH produced through pentose phosphate pathway (PPP). In cancer cells, this pathway can be regulated by the glycolytic enzyme pyruvate kinase M2 (PKM2) (2). In this study, the authors found that treat lung cancer cells A549 with H2O2, diamide (thiol-oxidizing compound) or hypoxia resulted in increasing ROS concentration and decreasing PKM2 activity, and can be restored by adding strong reducing agent dithiothreitol (DTT). Diamide treatment caused dissociation of PKM2 homotetramers and enzymatic activity inhibition by the oxidation of Cys358 instead of Cys31 and Cys 424. Replacement of Cys358 with Ser358 (C358S) resulted less sensitive to oxidant-induced inhibition. Using small molecule PKM2 activator DASA-10 could maintain PKM2 in an active conformation and prevent oxidation of Cys358-induced inhibition. This inhibition of PKM2 can divert glucose flux into PPP and generate reducing molecule for ROS detoxification. The C358S mutant cells, which were oxidation-resistant, exhibited increasing sensitivity to oxidative stress and decreasing tumor formation in the animal study. Here, authors showed that promoting PKM2 regulation to interfere cancer cell metabolism may be an appropriate approach for therapeutic purposes.

References:

1.      Wellen K. E. and Thompson C. B. (2010). Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell 40(2), 323-32.

2.      Christofk H. R., Vander Heiden M. G., Harris M. H., Ramanathan A., Gerszten R. E., Wei R., Fleming M. D., Schreiber S. L., Cantley L. C. (2008). The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452(7184), 230-233.