Nm23-H1 homologs suppress tumor cell motility and anchorage independent growth.
Nm23-H1 suppresses metastasis, as well as in vitro cell motility, invasion and anchorage independent growth, in a variety of cancer models. Eight human homologs of Nm23 have been identified that share 26-88% identity with the prototype Nm23-H1. Here, we examine the potential of its homologs, -H2, DR-, -H4 and -H5, to inhibit in vitro correlates of metastasis in two highly metastatic human cell lines, MDA-MB-435 and MDA-MB-231. The metastatic cells were transfected with mammalian expression constructs containing the genes encoding for Nm23-H1, -H2, DR-, -H4 and -H5 and the resultant transfectants were analyzed by Boyden chamber motility and soft agar colonization assays. Nm23-H1 suppressed motility by 3.3- and 1.5-fold in MDA-MB-435 and MDA-MB-231 cells, respectively and inhibited anchorage independent growth in soft agar by 2.9- and 1.9-fold, respectively. None of the -H1 homologs were capable of suppressing motility in MDA-MB-435 cells, but in MDA-MB-231 cells, -H2 inhibited motility by 3-fold upon overexpression. When anchorage independent growth was assessed, -H2, -H4 and -H5 suppressed growth from 1.2- to 2.0-fold in both cell lines. Given their ability to suppress anchorage independent growth, Nm23-H1 homologs -H2, -H4 and -H5 may have some capacity to suppress metastasis. Motility suppression appears to be cell context dependent, but sequence disparities between -H1/H2 and the other family members may reveal regions critical for this inhibitory phenotype. Similarly, sequence differences between DR-Nm23 and its homologs may be important for anchorage independent growth suppression.
Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NCI/NIH, 37 Convent Dr., Bethesda, MD 20892, USA.
William G
WG
McDermott
Mathieu
M
Boissan
Marie-Lise
ML
Lacombe
Patricia S
PS
Steeg
Christine E
CE
Horak
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics / Q000502:physiology*; D009362:Neoplasm Metastasis / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D054778:NM23 Nucleoside Diphosphate Kinases; C517938:NME1 protein, human