PMID- 22389449
OWN - NLM
STAT- MEDLINE
DCOM- 20120601
LR  - 20220408
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 72
IP  - 8
DP  - 2012 Apr 15
TI  - Expression of a truncated active form of VDAC1 in lung cancer associates with 
      hypoxic cell survival and correlates with progression to chemotherapy resistance.
PG  - 2140-50
LID - 10.1158/0008-5472.CAN-11-3940 [doi]
AB  - Resistance to chemotherapy-induced apoptosis of tumor cells represents a major 
      hurdle to efficient cancer therapy. Although resistance is a characteristic of 
      tumor cells that evolve in a low oxygen environment (hypoxia), the mechanisms 
      involved remain elusive. We observed that mitochondria of certain hypoxic cells 
      take on an enlarged appearance with reorganized cristae. In these cells, we found 
      that a major mitochondrial protein regulating metabolism and apoptosis, the 
      voltage-dependent anion channel 1 (VDAC1), was linked to chemoresistance when in 
      a truncated (VDAC1-DeltaC) but active form. The formation of truncated VDAC1, which 
      had a similar channel activity and voltage dependency as full-length, was 
      hypoxia-inducible factor-1 (HIF-1)-dependent and could be inhibited in the 
      presence of the tetracycline antibiotics doxycycline and minocycline, known 
      inhibitors of metalloproteases. Its formation was also reversible upon cell 
      reoxygenation and associated with cell survival through binding to the 
      antiapoptotic protein hexokinase. Hypoxic cells containing VDAC1-DeltaC were less 
      sensitive to staurosporine- and etoposide-induced cell death, and silencing of 
      VDAC1-DeltaC or treatment with the tetracycline antibiotics restored sensitivity. 
      Clinically, VDAC1-DeltaC was detected in tumor tissues of patients with lung 
      adenocarcinomas and was found more frequently in large and late-stage tumors. 
      Together, our findings show that via induction of VDAC1-DeltaC, HIF-1 confers 
      selective protection from apoptosis that allows maintenance of ATP and cell 
      survival in hypoxia. VDAC1-DeltaC may also hold promise as a biomarker for tumor 
      progression in chemotherapy-resistant patients.
FAU - Brahimi-Horn, M Christiane
AU  - Brahimi-Horn MC
AD  - Institute of Developmental Biology and Cancer Research, University of Nice, 
      CNRS-UMR 6543, Centre Antoine Lacassagne, Nice, France.
FAU - Ben-Hail, Danya
AU  - Ben-Hail D
FAU - Ilie, Marius
AU  - Ilie M
FAU - Gounon, Pierre
AU  - Gounon P
FAU - Rouleau, Matthieu
AU  - Rouleau M
FAU - Hofman, Veronique
AU  - Hofman V
FAU - Doyen, Jerome
AU  - Doyen J
FAU - Mari, Bernard
AU  - Mari B
FAU - Shoshan-Barmatz, Varda
AU  - Shoshan-Barmatz V
FAU - Hofman, Paul
AU  - Hofman P
FAU - Pouyssegur, Jacques
AU  - Pouyssegur J
FAU - Mazure, Nathalie M
AU  - Mazure NM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120302
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Protein Isoforms)
RN  - 0 (VDAC1 protein, human)
RN  - EC 1.6.- (Voltage-Dependent Anion Channel 1)
SB  - IM
MH  - Adenocarcinoma/metabolism/pathology
MH  - Apoptosis/physiology
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - Disease Progression
MH  - Drug Resistance, Neoplasm/*physiology
MH  - Female
MH  - Flow Cytometry
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Immunoblotting
MH  - Lung Neoplasms/*metabolism/pathology
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Staging
MH  - Protein Isoforms/metabolism
MH  - Transfection
MH  - Voltage-Dependent Anion Channel 1/*biosynthesis
EDAT- 2012/03/06 06:00
MHDA- 2012/06/02 06:00
CRDT- 2012/03/06 06:00
PHST- 2012/03/06 06:00 [entrez]
PHST- 2012/03/06 06:00 [pubmed]
PHST- 2012/06/02 06:00 [medline]
AID - 0008-5472.CAN-11-3940 [pii]
AID - 10.1158/0008-5472.CAN-11-3940 [doi]
PST - ppublish
SO  - Cancer Res. 2012 Apr 15;72(8):2140-50. doi: 10.1158/0008-5472.CAN-11-3940. Epub 
      2012 Mar 2.