PMID- 27661776
OWN - NLM
STAT- MEDLINE
DCOM- 20170515
LR  - 20191210
IS  - 1097-4652 (Electronic)
IS  - 0021-9541 (Linking)
VI  - 232
IP  - 6
DP  - 2017 Jun
TI  - Hypoglycemia Enhances Epithelial-Mesenchymal Transition and Invasiveness, and 
      Restrains the Warburg Phenotype, in Hypoxic HeLa Cell Cultures and 
      Microspheroids.
PG  - 1346-1359
LID - 10.1002/jcp.25617 [doi]
AB  - The accelerated growth of solid tumors leads to episodes of both hypoxia and 
      hypoglycemia (HH) affecting their intermediary metabolism, signal transduction, 
      and transcriptional activity. A previous study showed that normoxia (20% O(2) ) 
      plus 24 h hypoglycemia (2.5 mM glucose) increased glycolytic flux whereas 
      oxidative phosphorylation (OxPhos) was unchanged versus normoglycemia in HeLa 
      cells. However, the simultaneous effect of HH on energy metabolism has not been 
      yet examined. Therefore, the effect of hypoxia (0.1-1% O(2) ) plus hypoglycemia 
      on the energy metabolism of HeLa cells was analyzed by evaluating protein content 
      and activity, along with fluxes of both glycolysis and OxPhos. Under hypoxia, in 
      which cell growth ceased and OxPhos enzyme activities, DeltaPsim and flux were 
      depressed, hypoglycemia did not stimulate glycolytic flux despite increasing 
      H-RAS, p-AMPK, GLUT1, GLUT3, and HKI levels, and further decreasing mitochondrial 
      enzyme content. The impaired mitochondrial function in HH cells correlated with 
      mitophagy activation. The depressed OxPhos and unchanged glycolysis pattern was 
      also observed in quiescent cells from mature multicellular tumor spheroids, 
      suggesting that these inner cell layers are similarly subjected to HH. The 
      principal ATP supplier was glycolysis for HH 2D monolayer and 3D quiescent 
      spheroid cells. Accordingly, the glycolytic inhibitors iodoacetate and gossypol 
      were more effective than mitochondrial inhibitors in decreasing HH-cancer cell 
      viability. Under HH, stem cell-, angiogenic-, and EMT-biomarkers, as well as 
      glycoprotein-P content and invasiveness, were also enhanced. These observations 
      indicate that HH cancer cells develop an attenuated Warburg and pronounced EMT- 
      and invasive-phenotype. J. Cell. Physiol. 232: 1346-1359, 2017. (c) 2016 Wiley 
      Periodicals, Inc.
CI  - (c) 2016 Wiley Periodicals, Inc.
FAU - Marin-Hernandez, Alvaro
AU  - Marin-Hernandez A
AD  - Departamento de Bioquimica, Instituto Nacional de Cardiologia, Mexico, Mexico.
FAU - Gallardo-Perez, Juan Carlos
AU  - Gallardo-Perez JC
FAU - Hernandez-Resendiz, Ileana
AU  - Hernandez-Resendiz I
FAU - Del Mazo-Monsalvo, Isis
AU  - Del Mazo-Monsalvo I
FAU - Robledo-Cadena, Diana Xochiquetzal
AU  - Robledo-Cadena DX
FAU - Moreno-Sanchez, Rafael
AU  - Moreno-Sanchez R
FAU - Rodriguez-Enriquez, Sara
AU  - Rodriguez-Enriquez S
AD  - Departamento de Bioquimica, Instituto Nacional de Cardiologia, Mexico, Mexico.
LA  - eng
PT  - Journal Article
DEP - 20160930
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (Antineoplastic Agents)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - IY9XDZ35W2 (Glucose)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Adenosine Triphosphate/pharmacology
MH  - Antineoplastic Agents/pharmacology
MH  - Cell Hypoxia/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Energy Metabolism/drug effects
MH  - *Epithelial-Mesenchymal Transition/drug effects
MH  - Glucose/pharmacology
MH  - *Glycolysis/drug effects
MH  - HeLa Cells
MH  - Humans
MH  - Hypoglycemia/*pathology
MH  - Inhibitory Concentration 50
MH  - MCF-7 Cells
MH  - Mitochondria/drug effects/metabolism
MH  - Mitophagy/drug effects
MH  - Neoplasm Invasiveness
MH  - Oxygen/pharmacology
MH  - Phenotype
MH  - Spheroids, Cellular/drug effects/metabolism/*pathology
EDAT- 2016/09/24 06:00
MHDA- 2017/05/16 06:00
CRDT- 2016/09/24 06:00
PHST- 2016/07/14 00:00 [received]
PHST- 2016/09/22 00:00 [accepted]
PHST- 2016/09/24 06:00 [pubmed]
PHST- 2017/05/16 06:00 [medline]
PHST- 2016/09/24 06:00 [entrez]
AID - 10.1002/jcp.25617 [doi]
PST - ppublish
SO  - J Cell Physiol. 2017 Jun;232(6):1346-1359. doi: 10.1002/jcp.25617. Epub 2016 Sep 
      30.