Prevention of myeloma cell apoptosis by ectopic bcl-2 expression or interleukin 6-mediated up-regulation of bcl-XL

• Published in: Cancer research (Chicago, Ill.) Ill.), 1995-06, Vol.55 (11), p.2262-2265
• Main Authors: SCHWARZE, M. M. K, HAWLEY, R. G
• Format: Article
• Language: English
• Subjects: Ageing, cell death; Animals; Apoptosis - drug effects; Apoptosis - physiology; bcl-X Protein; Biological and medical sciences; Cell Death - drug effects; Cell Death - physiology; Cell physiology; DNA, Neoplasm - drug effects; DNA, Neoplasm - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - physiology; Interleukin-6 - pharmacology; Mice; Molecular and cellular biology; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-bcl-2; Signal Transduction - drug effects; Signal Transduction - physiology; Transduction, Genetic; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 0008-5472; 1538-7445

Upon cytokine withdrawal, interleukin (IL) 6-dependent murine plasmacytoma/hybridoma (myeloma) cells die in a way characteristic of apoptosis. Although gene transfer-mediated elevation in Bcl-2 protein levels has been demonstrated to repress a number of apoptotic death programs, it has been reported that ectopic bcl-2 expression is unable to prolong the survival of IL-6-deprived myeloma cells. In view of the recent identification of Bax as a protein that antagonizes the anti-apoptotic function of Bcl-2, we sought to determine whether the inability of transfected bcl-2 to protect against myeloma cell apoptosis might simply be due to insufficient levels of Bcl-2 protein produced to counteract this inhibitor. We show here that high-level expression of an exogenous bcl-2 gene, introduced into IL-6-dependent B9 myeloma cells via retroviral or bovine papilloma virus-based vectors, is indeed able to suppress apoptotic death following cytokine deprivation, with the extent of protection provided correlating with the amount of Bcl-2 protein synthesized in relation to the amount of endogenous Bax protein present in the cells. Of note, however, we found that IL-6-mediated suppression of B9 apoptosis does not involve induction of endogenous bcl-2 expression but is associated instead with the upregulation of cellular bcl-x mRNA and Bcl-xL protein. These results thus extend the apoptotic death mechanisms that are inhibitable by both bcl-2 and bcl-xL to include that operative in IL-6-dependent cells and suggest that apoptosis in other cell types using the gp130 subunit of the IL-6 receptor might also be bcl-2 regulable or bcl-xL dependent.