Critical role of CD40‐mediated autocrine tumor necrosis factor‐alpha in potentiation of cisplatin‐induced cytotoxicity in cancer cells

Activation of CD40, a member of the tumor necrosis factor receptor (TNF‐R) family, results in growth inhibition or apoptosis in some tumor cells, making CD40 a potential antitumor therapeutic target. Although it is known that CD40 is able to induce tumor necrosis factor‐alpha (TNF‐α) secretion and potentiate cisplatin’s anticancer activity, whether TNF‐α induction is involved in sensitizing cisplatin by CD40 has not been addressed. In this report, we provide evidence substantiating an important role of autocrine TNF‐α in potentiation of cisplatin‐induced apoptosis by recombinant soluble CD40 ligand (rsCD40L) in different human cancer cell lines. Activation of CD40 by rsCD40L induces two phases of autocrine TNF‐α: the rapid early phase involving p38 MAP kinase and the robust and persistent late phase through enhanced tnf‐α gene transcription. Blocking TNF‐α with either a specific TNFR1 siRNA or a neutralizing anti‐TNF‐α antibody dramatically attenuated the potentiation effect of rsCD40L on cisplatin‐induced cancer cell death. These results reveal an important role of TNF‐α induction in CD40’s chemosensitization activity and suggest that modulating TNF‐α autocrine from cancer cells is an effective option for increasing the anticancer value of chemotherapeutics such as cisplatin. ( Cancer Sci 2012; 103: 197–202)