Alteration of the Sphingomyelin/Ceramide Pathway Is Associated with Resistance of Human Breast Carcinoma MCF7 Cells to Tumor Necrosis Factor-α-mediated Cytotoxicity

This study shows that tumor necrosis factor-␣ failed to induce arachidonic acid release in p55-transfected resistant cells, suggesting that an alteration of phospholipase A2 activation may be associated with MCF7 cell resistance to TNF

Zhenzi Cai


Scholarcy highlights

  • § Recipient of a grant from the Institut de Formation Superieure BioMedicale and the Association pour la Recherche sur le Cancer
  • In contrast to the rapid progress that has been made in defining gene products capable of regulating tumor necrosis factor-␣-induced cell death, the knowledge of the molecular components involved in cell resistance to TNF remains limited
  • We attempted to delineate the functional role of some second messengers in the acquisition of tumor resistance to TNF by comparing a TNFsensitive human breast cancer cell line MCF7 with its R-A1 variant selected for resistance to TNF
  • This TNF-resistant variant derived from MCF7 was found to be susceptible to anti-Fas-induced cell lysis as well as to the chemotherapeutic drug adriamycin, compelling evidence that the intracellular cell death pathway is functional in these cells
  • As compared to the parental MCF7 cells, the resistance of R-A1 cells to TNF correlated with a low level of p55 TNF receptor expression and an absence of TNF signaling through TNF-Rs
  • Functional wild-type p55 receptor expression was reestablished in R-A1 cells by gene transfer as well as subsequent nuclear factor-␬B activation in response to TNF, these cells remained totally resistant to the cytotoxic action of TNF
  • Our data suggest that a selective defect in tumor necrosis factor-␣ signaling associated with an alteration in sphingomyelinase activation can, at least in part, confer resistance to TNF-induced cell death

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