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J Biol Chem, Vol. 273, Issue 44, 29002-29008, October 30, 1998

Analysis of Human Breast Adenocarcinoma MCF7 Resistance to Tumor Necrosis Factor-induced Cell Death
LACK OF CORRELATION BETWEEN JNK ACTIVATION AND CERAMIDE PATHWAY

Maya Ameyar, Azeddine Atfi^¶, Zhenzi Cai, Rodica Stancou, Vladimir Shatrov, Ali Bettaïeb^**, and Salem Chouaïb

From the  INSERM U487 Cytokines et Immunologie des Tumeurs Humaines, Institut Gustave Roussy, 94805 Villejuif, ^¶ INSERM U482, Institut Fédératif de Recherche du Centre Hospitalo-Universitaire Saint-Antoine, 75012 Paris, and ^** INSERM CJF 95-03, Institut Claudius Régaud, 31052 Toulouse, France

Considerable progress has been made in the understanding of tumor necrosis factor (TNF) signaling; however, the molecular and biochemical basis of tumor resistance to the cytotoxic action of TNF are still not definitively identified yet. Although a role of c-Jun N-terminal kinase (JNK) pathway has been suggested as an effector in TNF signaling, its exact relative contribution and its interaction with ceramide pathway and tumor resistance to TNF remain unknown. The relationship between JNK activation and human breast adenocarcinoma MCF7 resistance acquisition to the cytotoxic action of TNF was therefore investigated. We demonstrate that TNF triggers JNK activation in both TNF-sensitive MCF7 cells and its resistant derivative, RA1/1001. In addition, when MCF7 cells were stably transfected with mitogen-activated protein kinase kinase 4 (MKK4) dominant-negative cDNA or transiently transfected with a dominant-negative c-Jun mutant (TAM 67), their susceptibility to the cytotoxic action of TNF remains comparable with control cells. We also demonstrated that JNK activation does not require ceramide generation since in MCF7 cells transfected with a dominant-negative derivative of FADD (FADD-DN), which are resistant to the cytotoxic action of TNF, TNF induced JNK activation in the absence of ceramide generation. Furthermore, our data indicate that exogenous permeable synthetic ceramide C-6 induced the killing of MCF7 cells transfected with MKK4 dominant-negative cDNA. These results provide strong evidence indicating that tumor acquisition of resistance to the cytotoxic action of TNF may occur either independently or at a level downstream of JNK activation and suggest that JNK activation is not linked to ceramide pathway in TNF-mediated apoptosis.

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