Tumor suppression without differentiation or apoptosis by antisense cyclin D1 gene transfer in K1735 melanoma involves induction of p53, p21WAF1 and superoxide dismutases.
In mammalian cells, terminal differentiation is mutually exclusive with proliferation. However, resistance to differentiation-inducing therapy requires alternative strategies to control poorly responsive tumors. We now show that retroviral transfer of the antisense cyclin D1 gene to differentiation-refractory K1735 melanoma leads to loss of in vivo tumorigenicity, shortened replicative ability, induction of the tumor suppressor p53 protein and of the cdk-inhibitor p21WAF1, increased beta-galactosidase pH 6.0 activity, and elevation in the ratio of superoxide dismutases to peroxidases, all properties associated with replicative senescence. However, pigmentation and tyrosinase expression, characteristic of differentiated melanocytic cells or apoptosis-associated PARP cleavage, were not increased by antisense cyclin D1 transduction. Our data suggests that targetting cyclin D1 inhibition suppresses melanoma tumorigenicity by promoting a cytostatic differentiation-independent pathway, mediated by activation of p53 and anti-oxidant functions.
Rieber
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Instituto Venezolano de Investigaciones Cientificas (IVIC), Centre of Microbiology & Cell Biology, Tumor Cell Biology Laboratory, Apartado 21827, Caracas 1020 A, Venezuela. mrieber@pasteur.ivic.ve
Rieber
M S
MS
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016375:Antisense Elements (Genetics); D017209:Apoptosis; D002374:Catalase / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D005979:Glutathione Peroxidase / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D025521:Tumor Suppressor Proteins
D000975:Antioxidants; D016375:Antisense Elements (Genetics); C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D011065:Poly(ADP-ribose) Polymerases