New evidence shows that not only caveolin-1 may negatively regulate survival and apoptosis but also that stressful stimuli may, in turn, positively regulate caveolin-1 expression. This phenomenon was shown to occur in NIH-3T3 mouse fibroblasts exposed to subcytotoxic levels of hydrogen peroxide . Significant up-regulation of caveolin-1 was observed in mouse macrophages exposed to various unrelated apoptotic agents, including simvastatin, camptothecin, or glucose deprivation . In this case, caveolin-1 was found to co-localize with phosphatidylserine on the cell surface of the apoptotic cells, thus serving as an indicator of macrophage apoptosis. Other stress signals that were reported to increase caveolin-1 protein levels included exposure to various cytostatic drugs in lung cancer cells [45,126,127]. The acute up-regulation of caveolin-1 expression by chemother-apeutic drugs may be related to the constitutively elevated caveolin-1 levels observed in MDR human cancer cell lines [44,45,128,129] and the correlation of caveolin-1 expression with expression of the MDR1 gene in leukemic bone marrow leukocytes . Another stress condition reported to induce caveolin-1 protein levels in endothelial cells at G0/G1 cell-cycle phase is hypergravity stress . In the latter case, the up-regulation of caveolin-1 was associated with the redistribution of caveolin-1 to an intracellular compartment . Recently, caveolin-1 protein levels were found to be significantly increased, in a time-dependent manner, upon detachment of anoikis-resistant breast and MDR colon cancer cells . A related phenomenon was also shown by immunofluorescence staining of caveolin-1 in kidneys of acute renal failure rats in vivo, where high-intensity caveolin-1 expression was observed in injured proximal tubules that were losing basement membrane adhesion or were apoptotic, at one to four days after ischemia-reper-fusion .
The mechanisms involved in the regulation of caveolin-1 expression is response to stress are poorly understood. TNF-a- and IL-1-induced up-regulation of caveolin-1 in breast and ovarian carcinoma cells is mediated by the NFkB pathway . A more recent study provides strong evidence implicating FOXO transcription factors, known to be up-regulated upon oxidative stress, in the induction of caveolin-1 . Finally, p53 was also shown to act as a positive transcriptional regulator of caveolin-1 expression [60,135].
Taken together, these data indicate that caveolin-1 expression is regulated by various stress and apoptosis-inducing conditions, suggesting that caveolin-1 may play an important role in the physiological stress response of both normal and cancer cells. Additional experiments are required in order to determine the mechanisms involved in caveolin-1 regulation and whether caveolin was functioning as a pro-survival protein or alternatively, causing apoptosis in these cells.
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