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. 2016 Feb 3;7(18):25113–25124. doi: 10.18632/oncotarget.7159

Figure 5. Src and PDK independently suppress ROS production.

Figure 5

A. Inhibition of both Src and PDKs additively increases ROS levels. 4T1 cells transduced with WT or Src-resistant Y289F PDHA1 were treated with DCA (10 mM), followed by ROS measurement. Error bars represent S.D. *p < 0.05. B. A simplified view of glucose metabolic reprogramming in cancer. During glycolysis in cancer cells, a significant portion of glucose carbon is diverted to biosynthetic pathways to fuel cell proliferation. Entry of pyruvate into mitochondrial oxidative metabolism is mediated primarily by the PDH complex. In cancer cells, the great majority of pyruvate is converted to lactate and is kept away from mitochondria, which is in part due to inhibition of PDH. This metabolic feature allows cancer cells to evade over-production of ROS that are byproducts of mitochondrial oxidative metabolism, thereby acquiring resistance to pro-oxidant therapies and enhanced metastatic potential. Src and PDK independently inactivate PDH through direct tyrosine (Y) and serine (S) phosphorylation, respectively. Furthermore, ROS may activate Src, resulting in a negative feedback loop to restrain cellular oxidative stress (see discussion). Green arrows indicate the flow of glucose carbon. OXPHOS: oxidative phosphorylation.