We recently reported that shikonin and its analogs were a class of necroptotic inducers that could bypass cancer drug resistance. However, the molecular targets of shikonin are not known. Here, we showed that shikonin and its analogs are inhibitors of tumor-specific pyruvate kinase-M2 (PKM2), among which shikonin and its enantiomeric isomer alkannin were the most potent and showed promising selectivity, that is, shikonin and alkannin at concentrations that resulted in over 50% inhibition of PKM2 activity did not inhibit PKM1 and pyruvate kinase-L (PKL). Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-xL and A549) that primarily express PKM2. HeLa cells transfected with PKM1 showed reduced sensitivity to shikonin- or alkannin-induced cell death. To the best of our knowledge, shikonin and alkannin are the most potent and specific inhibitors to PKM2 reported so far. As PKM2 universally expresses in cancer cells and dictates the last rate-limiting step of glycolysis vital for cancer cell proliferation and survival, enantiomeric shikonin and alkannin may have potential in future clinical application.
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We thank BPS Bioscience Inc (San Diego, CA, USA) for technical support of their product—recombinant human PKM2. This work was supported in part by the China National 863 project (2007AA02Z143) to XH; China Natural Sciences Foundation projects (30772544, 81071802) to XH and the Fundamental Research Funds for the Central Universities, National Ministry of Education, China, to XH.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Oncogene website
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Chen, J., Xie, J., Jiang, Z. et al. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. Oncogene 30, 4297–4306 (2011). https://doi.org/10.1038/onc.2011.137
- pyruvate kinase-M2
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