- Short report
- Open Access
Activation of Akt protects cancer cells from growth inhibition induced by PKM2 knockdown
© Qin et al.; licensee BioMed Central Ltd. 2014
- Received: 1 December 2013
- Accepted: 14 March 2014
- Published: 15 April 2014
PKM2 is an attractive target for cancer therapy, however, for many cancer cells, PKM2 knockdown only leads to a modest impairment of survival and proliferation. It is not known whether PKM2 knockdown rewires cell signaling pathways in these “PKM2 knockdown resistant” cells, and whether the rewired pathways are needed for their survival.
In present study, we investigated the effects of PKM2 knockdown on cellular signaling pathways in “PKM2 knockdown resistant” cancer cells. We found that knockdown of PKM2 leads to activation of Akt. Furthermore, we revealed that activation of Akt in PKM2 knockdown cells is a result of glycolysis disruption. Inhibiton of PI3K-Akt signaling pathway leads to significant growth inhibition and apoptosis in PKM2 knockdown cells.
Overall, our results indicate that activation of Akt is necessary for the survival of PKM2 knockdown cells. Combing PKM2 knockdown with PI3K or Akt inhibitors may lead to a better chance to kill tumors. Our research may provide an unexpected opportunity for the development and implementation of drugs targeting cell metabolism and aberrant Akt signaling.
- H1299 Cell
- Pyruvate Kinase
- PI3K Inhibitor
- Knockdown Efficiency
- Metabolic Reprogram
H1299 cells are resistant to PKM2 knockdown induced growth inhibition
PKM2 knockdown induces activation of Akt signaling pathway
Activation of Akt signaling pathway in PKM2 knockdown cells is a result of glycolysis disruption
Inhibition of PI3K-Akt signaling pathway induces growth inhibition and cell death in Si-PKM cells
Pyruvate kinase, especially PKM2, has been shown to play an important role in the reprogramming and maintenance of altered metabolism in cancer cells. In addition to metabolic reprogramming, PKM2 has also been demonstrated to directly regulate gene expression and subsequent cell cycle progression. At the same time, many oncogenic signaling pathways promote the metabolic reprogramming of cancer cells. It is now well accepted that systems-level cross-talk between metabolism and signaling pathways is required in the maintenance of cancer cell homeostasis.
Akt is a positive regulator of PKM2. Akt activation leads to activation of mTOR1 through phosphorylation and inhibition of TSC2; mTOR activation induces HIF1α expression, and HIF1α in turn enhances PKM2 expression through collaboration with c-Myc–hnRNPs splicing regulators. Here we show that loss of PKM2 leads to activation of Akt signaling pathway. Activation of Akt signaling pathway in PKM2 knockdown cells is a result of glycolysis disruption, and is through the canonical PI3K-Akt signaling pathway.
Activation of Akt plays important roles in cancer resistance to different therapeutics. Here we show that resistance of cancer cells to PKM2 deprivation mediated cell death is also mediated by Akt signaling pathway. PI3K inhibitor suppress proliferation of PKM2 knockdown H1299 cells and induces apoptosis. PKM2 knockdown renders cancer cells exquisitely sensitive to Akt inhibition. This indicates PKM2 knockdown cells relies on p-Akt for their survival and proliferation.
In conclusion, we have established a potential role of PI3K-Akt signaling pathway for survival of PKM2 knockdown cancer cells. Combining PKM2 knockdown with Akt or PI3K inhibitor leads to a better chance to kill cancer cells. Thus, cancer signaling pathways should be taken into account when targeting metabolic pathways in treating cancers.
We thank Drs. Chenyang Zhao and Liming Wang from Cleveland Clinic Foundation for critical reading of this manuscript. This work is supported by grants NCET-08-0260 from Ministry of Education; grants 31371441 and 81173503 from The National Natural Science Foundation of China and 2009DFA30990 from Ministry of Science and Technology of the People's Republic of China; 0708WCGA149 from the Gansu Provincial Science and Technology to J.Y.; the Fundamental Research Funds for the Central Universities lzujbky-2011-35.
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