Hyporesponsiveness to growth factors is one of the fundamental characteristics of senescent cells. We previously reported that the up-regulation of caveolin attenuates the growth factor response and the subsequent downstream signal cascades in senescent human diploid fibroblasts (HDF). Therefore, in the present experiment, we investigated the modulation of caveolin status in senescent cells to determine the effect of caveolin on mitogenic signaling efficiency and cell cycling. We could sucessfully reduce the level of caveolin-1 in senescent HDFs using its antisense-oligonucleotides and small interfering RNA (siRNA), and this resulted in the restoration of normal growth factor responses, such as the increased phosphorylation of Erk, the nuclear translocation of p-Erk and the subsequent activation of p-Elk upon EGF stimulation. Moreover, DNA synthesis and the re-entry of senescent cells into cell cycle were resumed upon EGF stimulation concomitantly with decreases in p53 and p21. Moreover, by adjusting caveolin status in senescent cells, morphological shape can be regained like young cells. These morphological changes of senescent cells were induced by disruption of focal adhesion complexes and caveolin-1 in membrane.
Taken together, we conclude that the senescent phenotype including the loss of mitogenic signaling and morphological changes is strongly related to their elevated levels of caveolin-1. In consequence, it can be anticipated that a new field of study is about to open, aimed at developing strategies to overcome the senescence-related functional deterioration and morphological alterations.