Abstract
Purpose
The unique metabolic profile of cancer (aerobic glycolysis) is an attractive therapeutic target for cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, has been shown to reverse glycolytic phenotype and induce mitochondrion-dependent apoptosis. In the present study, we investigated the effects of S6 kinase 1 (S6K1) inhibition on DCA-induced cell death and the underlying mechanisms in breast cancer cells.
Methods
Cell death was evaluated by annexin V and PI staining. The synergistic effects of DCA and PF4708671 were assessed by isobologram analysis. Small interfering RNA (siRNA) was used for suppressing gene expression. The mRNA and protein levels were measured by RT-PCR and Western blot analysis, respectively.
Results
PF4708671, a selective inhibitor of S6K1, and knockdown of S6K1 with specific siRNA enhanced DCA-induced cell death. Interestingly, a combination of DCA/PF4708671 markedly reduced protein expression of a glycolytic enzyme, hexokinase 2 (HK2). Suppression of HK2 activity using specific siRNA and 2-deoxyglucose (2-DG) further enhanced cell sensitivity to DCA/PF4708671. Overexpression of Myc-tagged HK2 rescued cell death induced by DCA/PF4708671.
Conclusions
Based on these findings, we propose that inhibition of S6K1, in combination with the glycolytic inhibitor, DCA, provides effective cancer therapy.
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Acknowledgments
This research has been supported by grants from the Radiological Translational Research program Research Program (50451-2014), the National Nuclear R&D program and Basic Science Research Program (A111770) funded by the Ministry of Education, Science and Technology and the Radiation Bio-Resource Research Program of the Korea Institute of Radiological and Medical Sciences (No. 740802) in the Republic of Korea.
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Sung-Eun Hong and Kyung-Sub Shin have contributed equally to this study.
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Hong, SE., Shin, KS., Lee, YH. et al. Inhibition of S6K1 enhances dichloroacetate-induced cell death. J Cancer Res Clin Oncol 141, 1171–1179 (2015). https://doi.org/10.1007/s00432-014-1887-9
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DOI: https://doi.org/10.1007/s00432-014-1887-9