Caveolin-1 as a novel target of therapeutic activity of fenretinide in osteosarcoma and glioblastoma in vitro

Caveolin-1 is an essential structural constituent of caveolae implicated in mitogenic signalling, oncogenesis, angiogenesis, neurodegenerative diseases and senescence. It is highly expressed in some tumours in vivo and this is associated with increased tumour aggressiveness, metastatic potential and suppression of apoptosis. In prostate, pancreas, thyroid, aggressive breast and bladder carcinomas the increase in caveolin-1 expression is frequently associated with acquisition of multidrug resistance to chemotherapy. In this study we show for the first time a therapeutic activity by Fenretinide, a synthetic derivative of retinoic acid, in osteosarcoma and glioblastoma cells. Results show also for the first time that Caveolin-1 is a molecular target of Fenretinide in these tumours, where its expression is down-regulated by the drug. The mechanism is p53-independent. As the downstream target of caveolin-1 downregulation, first results seem to exclude the ERK/pERK MAP kinases pathway. In each cell line the caveolin-1 expression did correlate with a negative estrogen receptor phenotype, as evaluated in the cytosol: this is in the line with recent results by others, indicating a cause-effect relationship between a high Caveolin-1 expression and the loss of ER in the cytosol. The capability of fenretinide to target and down-regulate caveolin-1 may have a key role to decrease tumour aggressiveness and to re-establish chemosensitivity in these tumours.