title: Inhibition of S6K1 enhances dichloroacetate-induced cell death.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139-706, Republic of Korea.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Hong
authors.forename: Keong-Sub
authors.initials: KS
authors.lastname: Shin
authors.forename: Yun-Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Sung-Kum
authors.initials: SK
authors.lastname: Seo
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Yun
authors.forename: Tae-Boo
authors.initials: TB
authors.lastname: Choe
authors.forename: Hyun-Ah
authors.initials: HA
authors.lastname: Kim
authors.forename: Eun-Kyu
authors.initials: EK
authors.lastname: Kim
authors.forename: Woo Chul
authors.initials: WC
authors.lastname: Noh
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
authors.forename: Chang-Sun
authors.initials: CS
authors.lastname: Hwang
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Lee
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.forename: Hyeon-Ok
authors.initials: HO
authors.lastname: Jin
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D010879:Piperazines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; C552719:PF-4708671; D010879:Piperazines; D034741:RNA, Small Interfering; D003999:Dichloroacetic Acid; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1