PMID- 23195224
OWN - NLM
STAT- MEDLINE
DCOM- 20130319
LR  - 20191210
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1833
IP  - 3
DP  - 2013 Mar
TI  - Anti-mitochondrial therapy in human breast cancer multi-cellular spheroids.
PG  - 541-51
LID - S0167-4889(12)00334-5 [pii]
LID - 10.1016/j.bbamcr.2012.11.013 [doi]
AB  - During multi-cellular tumor spheroid growth, oxygen and nutrient gradients 
      develop inducing specific genetic and metabolic changes in the proliferative and 
      quiescent cellular layers. An integral analysis of proteomics, metabolomics, 
      kinetomics and fluxomics revealed that both proliferative- (PRL) and 
      quiescent-enriched (QS) cellular layers of mature breast tumor MCF-7 
      multi-cellular spheroids maintained similar glycolytic rates (3-5 nmol/min/10(6) 
      cells), correlating with similar GLUT1, GLUT3, PFK-1, and HKII contents, and HK 
      and LDH activities. Enhanced glycolytic fluxes in both cell layer fractions also 
      correlated with higher HIF-1alpha content, compared to MCF-7 monolayer cultures. On 
      the contrary, the contents of the mitochondrial proteins GA-K, ND1, COXIV, 
      PDH-E1alpha, 2-OGDH, SDH and F1-ATP synthase (20 times) and the oxidative 
      phosphorylation (OxPhos) flux (2-times) were higher in PRL vs. QS. Enhanced 
      mitochondrial metabolism in the PRL layers correlated with an increase in the 
      oncogenes h-Ras and c-Myc, and transcription factors p32 and PGC-1alpha, which are 
      involved in the OxPhos activation. On the other hand, the lower mitochondrial 
      function in QS was associated with an increase in Beclin, LC3B, Bnip3 and LAMP 
      protein levels, indicating active mitophagy and lysosome biosynthesis processes. 
      Although a substantial increase in glycolysis was developed, OxPhos was the 
      predominant ATP supplier in both QS and PRL layers. Therefore, targeted 
      anti-mitochondrial therapy by using oligomycin (IC(50)=11 nM), Casiopeina II-gly 
      (IC(50)=40 nM) or Mitoves (IC(50)=7 nM) was effective to arrest MCF-7 spheroid 
      growth without apparent effect on normal epithelial breast tissue at similar 
      doses; canonical anti-neoplastic drugs such as cisplatin and tamoxifen were 
      significantly less potent.
CI  - Copyright (c) 2012 Elsevier B.V. All rights reserved.
FAU - Mandujano-Tinoco, Edna Ayerim
AU  - Mandujano-Tinoco EA
AD  - Departamento de Bioquimica, Instituto Nacional de Cardiologia, Mexico.
FAU - Gallardo-Perez, Juan Carlos
AU  - Gallardo-Perez JC
FAU - Marin-Hernandez, Alvaro
AU  - Marin-Hernandez A
FAU - Moreno-Sanchez, Rafael
AU  - Moreno-Sanchez R
FAU - Rodriguez-Enriquez, Sara
AU  - Rodriguez-Enriquez S
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121127
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Oligomycins)
RN  - 0 (Organometallic Compounds)
RN  - 0 (Proteome)
RN  - 0 (Uncoupling Agents)
RN  - 0 (casiopeina II-glycine)
RN  - 789U1901C5 (Copper)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Blotting, Western
MH  - Breast/drug effects/metabolism
MH  - Breast Neoplasms/*drug therapy/metabolism/pathology
MH  - *Cell Proliferation
MH  - Copper/metabolism
MH  - Energy Metabolism/drug effects
MH  - Female
MH  - Glycolysis/drug effects
MH  - Humans
MH  - Immunoenzyme Techniques
MH  - Mitochondria/drug effects/metabolism
MH  - Mitochondrial Proteins/*metabolism
MH  - Mitophagy/*drug effects
MH  - Oligomycins/*pharmacology
MH  - Organometallic Compounds/*pharmacology
MH  - Oxidative Phosphorylation/drug effects
MH  - Proteome/analysis
MH  - Spheroids, Cellular/*drug effects/metabolism/pathology
MH  - Uncoupling Agents/pharmacology
EDAT- 2012/12/01 06:00
MHDA- 2013/03/21 06:00
CRDT- 2012/12/01 06:00
PHST- 2012/07/24 00:00 [received]
PHST- 2012/11/08 00:00 [revised]
PHST- 2012/11/15 00:00 [accepted]
PHST- 2012/12/01 06:00 [entrez]
PHST- 2012/12/01 06:00 [pubmed]
PHST- 2013/03/21 06:00 [medline]
AID - S0167-4889(12)00334-5 [pii]
AID - 10.1016/j.bbamcr.2012.11.013 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2013 Mar;1833(3):541-51. doi: 10.1016/j.bbamcr.2012.11.013. 
      Epub 2012 Nov 27.