Oxamflatin: a novel compound which reverses malignant phenotype to normal one via induction of JunD.
In the course of screening for inhibitors of tumorigenic phenotype of K-ras-transformed NIH3T3 cells (DT cells), we found a novel compound, oxamflatin, an aromatic sulfonamide hydroxamate derivative, which induces flat phenotype in these cells and suppresses their anchorage-independent growth. In contrast to DT cells, in v-raf-transformed NIH3T3 cells, no change in their morphology and no specific inhibition of their anchorage-independent growth was observed. Interestingly, oxamflatin was effective to NIH3T3 cells transformed by constitutively activated mutant of MEK, indicating the possibility that oncogene-induced morphological change is not necessarily induced by common signaling pathway such as MAP kinase cascade. In oxamflatin-treated DT cells, the expression of transcription factor junD was highly augmented, resulting in trans-activation of fibronectin gene by junD via cyclic AMP responsive element in its promoter. This behavior of junD was confirmed to correlate well with partial blocking of malignant phenotype in DT cells. Thus, oxamflatin can be categorized as the first reagent which induces genes whose products can interfere with oncogene-dependent transformation.
Sonoda
H
H
Shionogi Research Laboratories, Shionogi & Co.,Ltd., Osaka, Japan.
Nishida
K
K
Yoshioka
T
T
Ohtani
M
M
Sugita
K
K
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral / Q000187:drug effects*; D004789:Enzyme Activation; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015689:Oncogene Protein p21(ras) / Q000502:physiology; D027384:Oncogene Proteins v-raf; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D005353:Fibronectins; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D016755:Proto-Oncogene Proteins c-jun; D015682:Retroviridae Proteins, Oncogenic; C100692:oxamflatin; D027384:Oncogene Proteins v-raf; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D015689:Oncogene Protein p21(ras)