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Abstract In a number of human cancers, NTN1 upregulation inhibits apoptosis induced by its so‐called dependence receptors DCC and UNC5H, thus promoting tumor progression. In other cancers however, the selective inhibition of this dependence receptor death pathway relies on the silencing of pro‐apoptotic effector proteins. We show here that a substantial fraction of human breast tumors exhibits simultaneous DNA methylation‐dependent loss of expression of NTN1 and of DAPK1, a serine threonine kinase known to transduce the netrin‐1 dependence receptor pro‐apoptotic pathway. The inhibition of DNA methylation by drugs such as decitabine restores the expression of both NTN1 and DAPK1 in netrin‐1‐low cancer cells. Furthermore, a combination of decitabine with NTN1 silencing strategies or with an anti‐netrin‐1 neutralizing antibody potentiates tumor cell death and efficiently blocks tumor growth in different animal models. Thus, combining DNA methylation inhibitors with netrin‐1 neutralizing agents may be a valuable strategy for combating cancer.