Inhibition of tumor cell motility by the interferon-inducible GTPase MxA.
To identify pathways controlling prostate cancer metastasis we performed differential display analysis of the human prostate carcinoma cell line PC-3 and its highly metastatic derivative PC-3M. This revealed that a 78-kDa interferon-inducible GTPase, MxA, was expressed in PC-3 but not in PC-3M cells. The gene encoding MxA, MX1, is located in the region of chromosome 21 deleted as a consequence of fusion of TMPRSS2 and ERG, which has been associated with aggressive, invasive prostate cancer. Stable exogenous MxA expression inhibited in vitro motility and invasiveness of PC-3M cells. In vivo exogenous MxA expression decreased the number of hepatic metastases following intrasplenic injection. Exogenous MxA also reduced motility and invasiveness of highly metastatic LOX melanoma cells. A mutation in MxA that inactivated its GTPase reversed inhibition of motility and invasion in both tumor cell lines. Co-immunoprecipitation studies demonstrated that MxA associated with tubulin, but the GTPase-inactivating mutation blocked this association. Because MxA is a highly inducible gene, an MxA-targeted drug discovery screen was initiated by placing the MxA promoter upstream of a luciferase reporter. Examination of the NCI diversity set of small molecules revealed three hits that activated the promoter. In PC-3M cells, these drugs induced MxA protein and inhibited motility. These data demonstrate that MxA inhibits tumor cell motility and invasion, and that MxA expression can be induced by small molecules, potentially offering a new approach to the prevention and treatment of metastasis.
Mushinski
J Frederic
JF
Laboratory of Cancer Biology and Genetics, Medical Oncology Branch, Pediatric Oncology Branch, and Urologic Oncology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nguyen
Phuongmai
P
Stevens
Lisa M
LM
Khanna
Chand
C
Lee
Sunmin
S
Chung
Eun Joo
EJ
Lee
Min-Jung
MJ
Kim
Yeong Sang
YS
Linehan
W Marston
WM
Horisberger
Michel A
MA
Trepel
Jane B
JB
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000201:enzymology; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D064547:Myxovirus Resistance Proteins; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000032:analysis; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
D016898:Interferon-alpha; C579071:MX1 protein, human; D050505:Mutant Proteins; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D054852:Small Molecule Libraries; D014404:Tubulin; D019204:GTP-Binding Proteins