PMID- 29930749
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 9
IP  - 43
DP  - 2018 Jun 5
TI  - Hypoxia leads to decreased autophosphorylation of the MET receptor but promotes 
      its resistance to tyrosine kinase inhibitors.
PG  - 27039-27058
LID - 10.18632/oncotarget.25472 [doi]
AB  - The receptor tyrosine kinase MET and its ligand, the Hepatocyte Growth 
      Factor/Scattor Factor (HGF/SF), are essential to the migration, morphogenesis, 
      and survival of epithelial cells. In addition, dysregulation of MET signaling has 
      been shown to promote tumor progression and invasion in many cancers. Therefore, 
      HGF/SF and MET are major targets for chemotherapies. Improvement of targeted 
      therapies requires a perfect understanding of tumor microenvironment that 
      strongly modifies half-life, bio-accessibility and thus, efficacy of treatments. 
      In particular, hypoxia is a crucial microenvironmental phenomenon promoting 
      invasion and resistance to treatments. Under hypoxia, MET auto-phosphorylation 
      resulting from ligand stimulation or from receptor overexpression is drastically 
      decreased within minutes of oxygen deprivation but is quickly reversible upon 
      return to normoxia. Besides a decreased phosphorylation of its proximal adaptor 
      GAB1 under hypoxia, activation of the downstream kinases Erk and Akt is 
      maintained, while still being dependent on MET receptor. Consistently, several 
      cellular responses induced by HGF/SF, including motility, morphogenesis, and 
      survival are effectively induced under hypoxia. Interestingly, using a 
      semi-synthetic ligand, we show that HGF/SF binding to MET is strongly impaired 
      during hypoxia but can be quickly restored upon reoxygenation. Finally, we show 
      that two MET-targeting tyrosine kinase inhibitors (TKIs) are less efficient on 
      MET signalling under hypoxia. Like MET loss of phosphorylation, this 
      hypoxia-induced resistance to TKIs is reversible under normoxia. Thus, although 
      hypoxia does not affect downstream signaling or cellular responses induced by 
      MET, it causes immediate resistance to TKIs. These results may prove useful when 
      designing and evaluation of MET-targeted therapies against cancer.
FAU - Mekki, Meriem Sarah
AU  - Mekki MS
AD  - University Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of 
      Tumorigenesis and Target Therapies, F-59000 Lille, France.
FAU - Mougel, Alexandra
AU  - Mougel A
AD  - University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - 
      UMR 8204 - CIIL -Centre d'Infection et d'Immunite de Lille, F-59000 Lille, 
      France.
FAU - Vinchent, Audrey
AU  - Vinchent A
AD  - University Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of 
      Tumorigenesis and Target Therapies, F-59000 Lille, France.
FAU - Paquet, Charlotte
AU  - Paquet C
AD  - University Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of 
      Tumorigenesis and Target Therapies, F-59000 Lille, France.
FAU - Copin, Marie-Christine
AU  - Copin MC
AD  - University Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of 
      Tumorigenesis and Target Therapies, F-59000 Lille, France.
AD  - University Lille, Institut de Pathologie, CHU Lille, Avenue Oscar Lambret, 
      F-59000 Lille, France.
FAU - Leroy, Catherine
AU  - Leroy C
AD  - University Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of 
      Tumorigenesis and Target Therapies, F-59000 Lille, France.
FAU - Kherrouche, Zoulika
AU  - Kherrouche Z
AD  - University Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of 
      Tumorigenesis and Target Therapies, F-59000 Lille, France.
FAU - Bonte, Jean-Paul
AU  - Bonte JP
AD  - EA 4481 Faculte des Sciences Pharmaceutiques et Biologiques, Universite de Lille, 
      59006 Lille, France.
FAU - Melnyk, Oleg
AU  - Melnyk O
AD  - University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - 
      UMR 8204 - CIIL -Centre d'Infection et d'Immunite de Lille, F-59000 Lille, 
      France.
FAU - Vicogne, Jerome
AU  - Vicogne J
AD  - University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - 
      UMR 8204 - CIIL -Centre d'Infection et d'Immunite de Lille, F-59000 Lille, 
      France.
FAU - Tulasne, David
AU  - Tulasne D
AD  - University Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of 
      Tumorigenesis and Target Therapies, F-59000 Lille, France.
LA  - eng
PT  - Journal Article
DEP - 20180605
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC6007473
OTO - NOTNLM
OT  - MET
OT  - hepatocyte growth factor/scatter factor
OT  - hypoxia
OT  - receptor tyrosine kinase
OT  - tyrosine kinase inhibitor
COIS- CONFLICTS OF INTEREST The authors declare that there are no conflicts of 
      interest.
EDAT- 2018/06/23 06:00
MHDA- 2018/06/23 06:01
PMCR- 2018/06/05
CRDT- 2018/06/23 06:00
PHST- 2015/11/19 00:00 [received]
PHST- 2018/05/08 00:00 [accepted]
PHST- 2018/06/23 06:00 [entrez]
PHST- 2018/06/23 06:00 [pubmed]
PHST- 2018/06/23 06:01 [medline]
PHST- 2018/06/05 00:00 [pmc-release]
AID - 25472 [pii]
AID - 10.18632/oncotarget.25472 [doi]
PST - epublish
SO  - Oncotarget. 2018 Jun 5;9(43):27039-27058. doi: 10.18632/oncotarget.25472. 
      eCollection 2018 Jun 5.