PMID- 27479079
OWN - NLM
STAT- MEDLINE
DCOM- 20170822
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 8
DP  - 2016
TI  - Mild Alkalization Acutely Triggers the Warburg Effect by Enhancing Hexokinase 
      Activity via Voltage-Dependent Anion Channel Binding.
PG  - e0159529
LID - 10.1371/journal.pone.0159529 [doi]
LID - e0159529
AB  - To fully understand the glycolytic behavior of cancer cells, it is important to 
      recognize how it is linked to pH dynamics. Here, we evaluated the acute effects 
      of mild acidification and alkalization on cancer cell glucose uptake and 
      glycolytic flux and investigated the role of hexokinase (HK). Cancer cells 
      exposed to buffers with graded pH were measured for 18F-fluorodeoxyglucose (FDG) 
      uptake, lactate production and HK activity. Subcellular localization of HK 
      protein was assessed by western blots and confocal microscopy. The interior of 
      T47D breast cancer cells was mildly alkalized to pH 7.5 by a buffer pH of 7.8, 
      and this was accompanied by rapid increases of FDG uptake and lactate extrusion. 
      This shift toward glycolytic flux led to the prompt recovery of a reversed pH 
      gradient. In contrast, mild acidification rapidly reduced cellular FDG uptake and 
      lactate production. Mild acidification decreased and mild alkalization increased 
      mitochondrial HK translocation and enzyme activity. Cells transfected with 
      specific siRNA against HK-1, HK-2 and voltage-dependent anion channel (VDAC)1 
      displayed significant attenuation of pH-induced changes in FDG uptake. Confocal 
      microscopy showed increased co-localization of HK-1 and HK-2 with VDAC1 by 
      alkaline treatment. In isolated mitochondria, acidic pH increased and alkaline pH 
      decreased release of free HK-1 and HK-2 from the mitochondrial pellet into the 
      supernatant. Furthermore, experiments using purified proteins showed that 
      alkaline pH promoted co-immunoprecipitation of HK with VDAC protein. These 
      findings demonstrate that mild alkalization is sufficient to acutely trigger 
      cancer cell glycolytic flux through enhanced activity of HK by promoting its 
      mitochondrial translocation and VDAC binding. This process might serve as a 
      mechanism through which cancer cells trigger the Warburg effect to maintain a 
      dysregulated pH.
FAU - Quach, Cung Hoa Thien
AU  - Quach CH
AD  - Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea.
FAU - Jung, Kyung-Ho
AU  - Jung KH
AD  - Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea.
AD  - Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan 
      University School of Medicine, Seoul, Korea.
FAU - Lee, Jin Hee
AU  - Lee JH
AD  - Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea.
AD  - Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan 
      University School of Medicine, Seoul, Korea.
FAU - Park, Jin Won
AU  - Park JW
AD  - Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea.
AD  - Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan 
      University School of Medicine, Seoul, Korea.
FAU - Moon, Seung Hwan
AU  - Moon SH
AD  - Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea.
FAU - Cho, Young Seok
AU  - Cho YS
AD  - Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea.
FAU - Choe, Yearn Seong
AU  - Choe YS
AD  - Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea.
AD  - Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan 
      University School of Medicine, Seoul, Korea.
FAU - Lee, Kyung-Han
AU  - Lee KH
AD  - Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea.
AD  - Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan 
      University School of Medicine, Seoul, Korea.
LA  - eng
PT  - Journal Article
DEP - 20160801
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (RNA, Small Interfering)
RN  - 0 (VDAC1 protein, human)
RN  - 0Z5B2CJX4D (Fluorodeoxyglucose F18)
RN  - 33X04XA5AT (Lactic Acid)
RN  - EC 1.6.- (Voltage-Dependent Anion Channel 1)
RN  - EC 2.7.1.1 (HK1 protein, human)
RN  - EC 2.7.1.1 (Hexokinase)
SB  - IM
MH  - Cell Line, Tumor
MH  - Fluorodeoxyglucose F18/metabolism
MH  - Glycolysis
MH  - Hexokinase/antagonists & inhibitors/genetics/*metabolism
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Immunoprecipitation
MH  - Lactic Acid/metabolism
MH  - Microscopy, Confocal
MH  - Mitochondria/metabolism
MH  - Protein Binding
MH  - RNA Interference
MH  - RNA, Small Interfering/metabolism
MH  - Voltage-Dependent Anion Channel 1/antagonists & inhibitors/genetics/*metabolism
PMC - PMC4968818
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2016/08/02 06:00
MHDA- 2017/08/23 06:00
PMCR- 2016/08/01
CRDT- 2016/08/02 06:00
PHST- 2016/02/22 00:00 [received]
PHST- 2016/07/05 00:00 [accepted]
PHST- 2016/08/02 06:00 [entrez]
PHST- 2016/08/02 06:00 [pubmed]
PHST- 2017/08/23 06:00 [medline]
PHST- 2016/08/01 00:00 [pmc-release]
AID - PONE-D-16-07528 [pii]
AID - 10.1371/journal.pone.0159529 [doi]
PST - epublish
SO  - PLoS One. 2016 Aug 1;11(8):e0159529. doi: 10.1371/journal.pone.0159529. 
      eCollection 2016.