Suppression of tumorigenic and metastatic potentials of human melanoma cell lines by mutated (143 Val-Ala) p53.
Metastatic melanoma, compared with other cancers, appears to be unusual because of its low frequency of p53 mutations and prevalence of wild-type p53 protein in advanced malignancy. Here, we examined the effects of wild-type and mutated p53 (143 Val-Ala) on tumorigenic and metastatic potential of two human melanoma cell lines. The cell line UISO-MEL-4 contains wild-type p53 and is tumorigenic, whereas UISO-MEL-6 lacks p53 and produces lung and liver metastasis upon s.c. injection into athymic mice. Our study showed that UISO-MEL-4 stably transfected with wild-type p53 cDNA driven by cytomegalovirus promoter-enhancer sequences expressed high levels of p53 and p21 and formed s.c. tumours in vivo. Mutated p53 (143 Val-Ala) expression, on the other hand, inhibited tumour growth in 50% of cases and produced significantly slower growing non-metastatic tumours. Reduced tumour growth involved necrotic as well as apoptotic cell death. Inhibition of tumour growth was abrogated by the addition of Matrigel (15 mg ml(-1)). With UISO-MEL-6 cells, stably transfected with mutant p53, tumour growth was delayed and metastasis was inhibited. In soft agar colony formation assay, both wild-type and mutant p53 transfectants reduced anchorage-independent colony formation in vitro. These data suggest that mutated (143 Val-Ala) p53, which retains DNA binding and some of the transactivation functions of the wild-type p53 protein, suppresses tumorigenic and metastatic potentials of human melanoma cell lines in vivo.
Rauth
S
S
Department of Surgical Oncology, University of Illinois at Chicago, 60612, USA.
Green
A
A
Kichina
J
J
Shilkaitis
A
A
D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003094:Collagen / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D015870:Gene Expression; D016158:Genes, p53; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008545:Melanoma / Q000235:genetics / Q000473:pathology* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009368:Neoplasm Transplantation; D011509:Proteoglycans / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D001672:Biocompatible Materials; D004273:DNA, Neoplasm; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D016159:Tumor Suppressor Protein p53; C059485:matrigel; D003094:Collagen