Expression of BCL-2 protein enhances the survival of mouse fibrosarcoid cells in tumor necrosis factor-mediated cytotoxicity.
Tumor necrosis factor (TNF) kills some types of tumor cells in vitro and participates in tumor elimination in vivo. TNF has been shown to kill cells by altering their mitochondria structurally and functionally. The oncogene BCL-2 codes for a protein located in the inner membrane of mitochondria which is able to inhibit the commitment to cell death in various cell types. We have therefore investigated whether TNF-mediated killing of the cell line L929 could be modulated by expression of the protein BCL-2. We report here that L929 cells transfected with a BCL-2 expression vector have an increased survival compared to wild type cells after TNF challenge. The protective effect is greatest at moderate TNF concentrations and is still significant at concentrations that killed 100% of wild type cells. The action of BCL-2 is selective inasmuch as cells are not protected against other cytotoxic agents blocking various mitochondrial functions. We show that cells expressing BCL-2 have a higher mitochondrial membrane potential (delta psi) than wild type cells. The increase in delta psi could be linked with the enhanced survival of cells after TNF challenge. Indeed, we found that treatment of wild type L929 cells with the ionophore nigericin, which increases delta psi, protects them even at high TNF concentrations.
Hennet
T
T
Institute of Veterinary Virology, University of Berne, Switzerland.
Bertoni
G
G
Richter
C
C
Peterhans
E
E
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D009550:Nigericin / Q000494:pharmacology; D010101:Oxygen Consumption; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D009550:Nigericin