M. Giampuzzi et al., Down-regulation of lysyl oxidase-induced tumorigenic transformation in NRK-49F cells characterized by constitutive activation of Ras proto-oncogene, J BIOL CHEM, 276(31), 2001, pp. 29226-29232
Several investigations have suggested a putative tumor suppressor role for
lysyl oxidase because it is downregulated in many human and oncogene-induce
d tumors. To address this issue we down-regulated the enzyme in normal rat
kidney fibroblasts by stable transfection of its cDNA in an antisense orien
tation. The selected clones revealed an absence of lysyl oxidase and dramat
ic phenotypic changes, interpretable as signs of transformation. The antise
nse lysyl oxidase clones showed, indeed, loose attachment to the plate and
anchorage-independent growth and were highly tumorigenic in nude mice. More
over, we found an impaired response of the PDGF and IGF-1 receptors to thei
r ligands. In particular, the transformed cells showed a down-regulation of
both PDGF receptors and expressed the 105-kDa isoform of the IGF-1 beta re
ceptor, which was not present in the normal control cells. The lack of resp
onse to PDGF-BB has been described as a feature of many ras-transformed phe
notypes. Therefore, we looked at the status of the p21(ras). Indeed, we fou
nd a significantly higher level of active p21(ras) both during steady-state
growth and prolonged starvation. Our data reveal new evidence for a tumor
suppressor activity of lysyl oxidase, highlighting its particular role in c
ontrolling Ras activation and growth factor dependence.