期刊
EMBO MOLECULAR MEDICINE
卷 5, 期 12, 页码 1821-1834出版社
WILEY-BLACKWELL
DOI: 10.1002/emmm.201302654
关键词
cancer therapy; DCC; dependence receptor; netrin-1; p53
资金
- CNRS
- Centre Leon Berard
- Ligue Contre le Cancer, INCA, ERC, LABEX DEVweCAN of Universite de Lyon [ANR-10-LABX-0061, ANR-11-IDEX-0007]
- Agence Nationale de la Recherche (ANR) [ANR-10-LABX-0061] Funding Source: Agence Nationale de la Recherche (ANR)
The secreted factor netrin-1 is upregulated in a fraction of human cancers as a mechanism to block apoptosis induced by netrin-1 dependence receptors DCC and UNC5H. Targeted therapies aiming to trigger tumour cell death via netrin-1/receptors interaction interference are under preclinical evaluation. We show here that Doxorubicin, 5-Fluorouracil, Paclitaxel and Cisplatin treatments trigger, in various human cancer cell lines, an increase of netrin-1 expression which is accompanied by netrin-1 receptors increase. This netrin-1 upregulation which appears to be p53-dependent is a survival mechanism as netrin-1 silencing by siRNA is associated with a potentiation of cancer cell death upon Doxorubicin treatment. We show that candidate drugs interfering with netrin-1/netrin-1 receptors interactions potentiate Doxorubicin, Cisplatin or 5-Fluorouracil-induced cancer cell death in vitro. Moreover, in a model of xenografted nude mice, we show that systemic Doxorubicin treatment triggers netrin-1 upregulation in the tumour but not in normal organs, enhancing and prolonging tumour growth inhibiting effect of a netrin-1 interfering drug. Together these data suggest that combining conventional chemotherapies with netrin-1 interference could be a promising therapeutic approach.
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