Bcl-2 plays a major role in resistance to dexamethasone induced apoptosis in multiple myeloma cell lines

Abstract

The role of bcl-2 in protection against apoptosis is well established in a great variety of cells and has become a hallmark of drug-resistance in many tumor cell lines, notably in lymphomas and leukemias. However, the role of bcl-2 in spontaneous and drug induced apoptosis in multiple myeloma (MM), is not yet established, particularly since the frequency of t(14:18) in MM is relatively low. We have recently studied the steady-state levels of mRNA transcripts for bcl-2, bar and P53 in 8 MM cell lines and found inverse correlation between the levels of bcl-2 mRNA transcripts and sensitivity to dexamethasone (DEX) induced apoptosis. Moreover, we have also shown that mRNA transcripts for bcl-2 were further down-regulated in 2 DEX sensitive cell lines in the course of DEX induced apoptosis, whereas mRNA transcripts for bcl-2 were unchanged in 2 DEX-resistant MM cell lines (Int J Oncol 8: 719-726, 1996). In this study, we determined the steady-state levels of bcl-2, P53 and bar proteins in 4 myeloma cell lines, and the levels were correlated with sensitivity to DEX induced apoptosis. Two cell lines (HS-Sultan and ARH-77) expressed relatively high levels of bcl-2 protein and were highly resistant to DEX induced apoptosis. Two cell lines (8226 and ARP-1) expressed relatively low levels of bcl-2 protein, and were 2-3 logs more sensitive to DEX. In contrast, the levels of bar protein were similar in all cell lines tested. The steady-state levels of P53 protein varied among the various cell lines but did not correlate with resistance to DEX. Induction of apoptosis in the DEX sensitive cells resulted in an early down-regulation of bcl-2 and P53 protein, whereas the levels of bar protein were only slightly decreased. In contrast to the DEX sensitive cell lines, the levels of bcl-2, bar and P53 proteins in the DEX resistant cell lines were unchanged during 72 h of treatment with DEX. Thus, the changes in the protein levels are in good agreement with the changes reported earlier for mRNA transcript of these oncogenes.