A point mutation (G574A) in the chemokine receptor CXCR4 detected in human cancer cells enhances migration.
The chemokine receptor CXCR4 is widely expressed in human cancers and regulates cell invasion, proliferation and survival. Because mutations in the CXCR4 gene could regulate its function we sequenced the coding region of the CXCR4 gene in 18 human melanoma and 3 human colon carcinoma cell lines. The same somatic point mutation (G574A; V160I) in the fourth transmembrane region of CXCR4 was detected in one colon cancer cell line (PD) and one melanoma cell line (LB). CXCR4 was expressed and functional in both PD and LB cells, PD and LB cells migrated specifically toward the receptor ligand, CXCL12 and P-Erk was specifically induced by CXCL12. To give insight into the function of the mutant CXCR4 receptor, human A431, epidermoid carcinoma cells, were stably transfected with both mutant and wild type CXCR4. In vitro, A431 cells harboring CXCR4(G574A) migrated specifically toward CXCL12 and CXCL12 induced ERK phosphorylation. Interestingly, in vivo studies showed that the growth of A431 tumors harboring CXCR4(G574A) was delayed compared to those harboring WT CXCR4. As expected, treatment with AMD3100, a specific CXCR4 inhibitor, reduced the in vivo growth of CXCR4(G574A) tumor b(G574A) but surprisingly, increased the growth of CXCR4(G574A) A431 cells. This is the first report of a spontaneously occurring, functionally active CXCR4 mutation in human cancer cells. While the mutation impairs cell growth in vivo, the CXCR4 inhibitor, AMD3100, stimulated the growth of cells harboring CXCR4(G574A).
Ierano
Caterina
C
Clinical Immunology, The G. Pascale National Cancer Institute, Fondazione G. Pascale, Via Mariano Semola, Naples, Italy.
Giuliano
Paola
P
D'Alterio
Crescenzo
C
Cioffi
Michele
M
Mettivier
Valentina
V
Portella
Luigi
L
Napolitano
Maria
M
Barbieri
Antonio
A
Arra
Claudio
C
Liguori
Giuseppina
G
Franco
Renato
R
Palmieri
Giuseppe
G
Rozzo
Carla
C
Pacelli
Roberto
R
Castello
Giuseppe
G
Scala
Stefania
S
D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D005998:Glycine / Q000235:genetics; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D017354:Point Mutation / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000235:genetics*
C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D050505:Mutant Proteins; D019718:Receptors, CXCR4; D000409:Alanine; D005998:Glycine