Tumor development is initiated by a multiplicity of genetic abnormalities. Tumor cells need to escape barriers that limit uncontrolled cell proliferation. One of these barriers is represented by cellular senescence. Cancer cells need to overcome this obstacle to produce a clinically relevant tumor mass. For these reasons, cellular senescence represents a natural tumor suppressor mechanism. Thus, molecules that regulate cellular senescence are potential therapeutic targets for the treatment of cancer and the fight against aging.
Caveolae are invaginations of the plasma membrane enriched in cholesterol. Caveolin-1, the structural protein component of caveolar membranes, acts as a scaffolding protein to concentrate and functionally regulate signaling molecules.
In recent years, several independent lines of evidence have emerged suggesting that caveolin-1 may function as a "tumor suppressor protein" in mammalian cells. For example, caveolin-1 protein expression has been shown to be absent in several transformed cell lines derived from human mammary carcinomas, including MCF-7. In addition, caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes, such as v-Abl and H-ras (G12V); caveolae are absent from these cell lines. In addition, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (D7S522; 7q31.1), a known fragile site (FRA7G) that is deleted in many types of cancer.
Oxidative stress is a known inducer of cellular senescence. We have shown that up-regulation of caveolin-1 is required for oxidative stress–induced cellular senescence in fibroblasts. To unravel the molecular mechanisms underlying oxidative stress-induced up-regulation of caveolin-1 in senescent cells, Dr. Volonte has shown that oxidants stimulate the activity of the caveolin-1 promoter reporter gene construct in fibroblasts. She has identified Sp1 binding to two GC-boxes as the core mechanism of oxidative stress–triggered caveolin-1 transactivation. In addition, through signaling studies she has shown p38 mitogen-activated protein kinase (MAPK) as the upstream regulator of Sp1-mediated activation of the caveolin-1 promoter following oxidative stress. For the first time Dr. Volonte has delineated the molecular mechanisms that modulate caveolin-1 gene transcription upon oxidative stress bringing new insights into the redox control of cellular senescence in both normal and cancer cells.
Thus, cellular senescence may represent one of the molecular mechanisms through which caveolin-1 acts as a tumor suppressor protein. Current efforts are aimed at identifying the signaling molecules which link caveolin-1’s function to cellular senescence.
Volonte D and F Galbiati. Polymerase I and transcript release factor (PTRF)/cavin-1, a novel regulator of stress-induced premature senescence. J Biol Chem 286:28657-28661, 2011.