Attenuation of genotoxicity under adhesion-restrictive conditions through modulation of p53, gamma H2AX and nuclear DNA organization.
Interactions between tumor cells and their substratum influence cancer progression by modulating cell proliferation and survival. We now investigated whether signaling responses to UV irradiation differ on adhesion-permissive or restrictive substrates. The latter conditions diminished spreading and proliferation of neo 6.3/C8161 melanoma in which metastasis is suppressed by introduction of neo-tagged chromosome 6, but permitted proliferation of human metastatic C8161 melanoma. Apoptosis-associated PARP cleavage and DNA fragmentation induced by UV irradiation were diminished on the restrictive substrate in C8161 melanoma. Genotoxic responses to UV irradiation like persistent increases in the phosphorylation of histone H2AX, induction of the tumor suppressor p53 protein and greater binding of this protein to its DNA consensus sequence, were all decreased on the restrictive substrate. The latter also promoted a 2 fold increase of DNA condensation in chromatin and enhanced activation of the survival - and invasion-associated MMP-9 gelatinase B, preferentially in metastatic C81261 melanoma. Our data suggest that adaptation to restrictive substrates in metastatic C8161 melanoma decreases UV-induced apoptosis, partly through attenuation of DNA damage signaling responses and changes in genomic organization.
Strasberg Rieber
Mary
M
IVIC, Tumor Cell Biology Laboratory, CMBC, Apartado 21827, Caracas, Venezuela. mrieber@pasteur.ivic.ve
Viola-Rhenals
Maricela
M
Rieber
Manuel
M
D001483:Base Sequence; D002448:Cell Adhesion / Q000528:radiation effects; D002467:Cell Nucleus / Q000378:metabolism* / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002843:Chromatin / Q000378:metabolism / Q000528:radiation effects; D016384:Consensus Sequence; D019938:Cyclin D1 / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D053938:DNA Fragmentation / Q000528:radiation effects; D004790:Enzyme Induction / Q000528:radiation effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000528:radiation effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding / Q000528:radiation effects; D011499:Protein Processing, Post-Translational / Q000528:radiation effects; D013379:Substrate Specificity / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
D002843:Chromatin; C468783:H2AX protein, human; D006657:Histones; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D020780:Matrix Metalloproteinase 9