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. This protein acts as an oncosuppressor in some tumours in vivo like not aggressive breast and ovary carcinomas, sarcomas and leukemia. It is highly expressed and acts as a promoter in several others tumours in vivo like thyroid, prostate, bladder and pancreas carcinomas and in aggressive breast cancers where it is associated with high risk of metastasis and apoptosis suppression. The increase in caveolin-1 expression is frequently associated in these tumours with the 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 MG-63 and HOS osteosarcoma and A-172,LI,CRS-A2 glioblastoma cells, at doses identical to or lower than those detectable in patient’s plasma during chemopreventive clinical trials. In the MG- 63 and HOS osteosarcoma cells and in the CRS-A2 glioblastoma cells apoptosis was evident.The mechanism is mediated by pRB dephosphorylation in osteosarcoma, where it is p53 independent. Results show for the first time that Caveolin-1 is expressed either in osteosarcoma and in glioblastoma cell lines. They show also that caveolin-1 is a novel molecular target of Fenretinide in these tumours, where its expression is down-regulated by the drug. As the downstream target of caveolin-1 downregulation, first results seem to exclude the ERK/pERK MAP kinases pathway. Caveolin-1 mRNA expression, evaluated by RT-PCR, is not affected by the treatment with fenretinide, indicating an involvement of caveolin-1 at the protein level. In each cell line the caveolin-1 expression does 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.