The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling.
MET, the receptor for hepatocyte growth factor (HGF), plays an important role in signaling normal and tumor cell migration and invasion. Here, we describe a previously unrecognized mechanism that promotes MET expression in multiple tumor cell types. The levels of the Pim-1 protein kinase show a positive correlation with the levels of MET protein in human tumor cell lines and patient-derived tumor materials. Using small interfering RNA (siRNA), Pim knockout mice, small-molecule inhibitors, and overexpression of Pim-1, we confirmed this correlation and found that Pim-1 kinase activity regulates HGF-induced tumor cell migration, invasion, and cell scattering. The novel biochemical mechanism for these effects involves the ability of Pim-1 to control the translation of MET by regulating the phosphorylation of eukaryotic initiation factor 4B (eIF4B) on S406. This targeted phosphorylation is required for the binding of eIF4B to the eIF3 translation initiation complex. Importantly, Pim-1 action was validated by the evaluation of patient blood and bone marrow from a phase I clinical trial of a Pim kinase inhibitor, AZD1208. These results suggest that Pim inhibitors may have an important role in the treatment of patients where MET is driving tumor biology.
Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA The Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA cen@musc.edu kraft@musc.edu.
Bo
B
Cen
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Ying
Y
Xiong
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA The Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
Jin H
JH
Song
The Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
Sandeep
S
Mahajan
Oncology iMed, AstraZeneca, Waltham, Massachusetts, USA.
Rachel
R
DuPont
Oncology iMed, AstraZeneca, Waltham, Massachusetts, USA.
Kristen
K
McEachern
Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Daniel J
DJ
DeAngelo
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Jorge E
JE
Cortes
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Mark D
MD
Minden
Genentech, Inc., South San Francisco, California, USA.
Allen
A
Ebens
Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Alice
A
Mims
The Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA Research Services, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA.
Amanda C
AC
LaRue
Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA The Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA cen@musc.edu kraft@musc.edu.
Andrew S
AS
Kraft
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics; D039642:Eukaryotic Initiation Factors / Q000235:genetics*; D006367:HeLa Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D053778:Thiazolidines / Q000494:pharmacology
C587575:AZD1208; D001713:Biphenyl Compounds; D039621:Eukaryotic Initiation Factor-3; D039642:Eukaryotic Initiation Factors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D053778:Thiazolidines; C031799:eIF-4B; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C496636:Pim1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1