THE ROLE OF P53, BCL-2 AND BAX NETWORK IN DEXAMETHASONE-INDUCED APOPTOSIS IN MULTIPLE-MYELOMA CELL-LINES

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-resistan ce in many tumor cell lines, notably in lymphomas and leukemias. Confl icting results have been reported as for the role of bcl-2 in spontane ous and drug induced apoptosis in multiple myeloma (MM), although high expression of bcl-2 was observed, in spite of relatively low frequenc y of t(14:18). We, therefore, decided to conduct a detailed study of t he role of the bcl-2/bax/p53 network in dexamethasone (DEX) induced ap optosis in MM cells. Eight myeloma cell lines were screened for their expression of mRNA transcripts for p53, bcl-2 and bar, and the levels were correlated for sensitivity to DEX induced apoptosis. Two cell lin es (HS-Sultan and ARH-77) expressed relatively high levels of bcl-2 tr anscripts, and were highly resistant to DEX induced apoptosis (up to 1 0 mu M). Two cell lines (8226 and ARP-1) expressed relatively low-leve ls of bcl-2 mRNA transcripts, and were highly sensitive to DEX (ID50= 0.1 mu M, at 24-48 h). Fax mRNA transcripts were abundant, were expres sed ubiquitously in all cell lines, and, thus, did not correlate with sensitivity to DEX. The level of expression of mRNA transcripts for p5 3 varied among the various cell lines, and did not always correlate wi th resistance to DEX. Induction of apoptosis in 8226 and ARP-1 cells ( DEX sensitive) resulted, within 24 h, in a transient but marked down-r egulation of mRNA transcripts for bcl-2 and p53, whereas the level of expression of bar mRNA transcripts were unchanged, except for ARP-1 ce lls (lacking p53), where slight down-regulation of mRNA transcripts fo r bar, was observed. In contrast to the DEX sensitive cell lines, the level of expression of bcl-2, bax and p53 mRNA transcripts in the DEX resistant cell lines, were unchanged during 72 h of treatment with DEX (up to 10 mu M). We, therefore, conclude that bcl-2 and perhaps p53 a re involved in resistance to DEX in myeloma cell lines.