DEXAMETHASONE INDUCES APOPTOSIS OF MULTIPLE-MYELOMA CELLS IN A JNK SAP KINASE INDEPENDENT MECHANISM/

The stress-activated protein kinases (SAPKs), also known as c-Jun amin o-terminal kinases (JNKs), are activated in response to diverse stimul i including DNA damage, heat shock, interleukin-1, tumor necrosis fact or-alpha and Fas, Although all these inducers cause apoptosis, whether SAPK/JNK activation is required for apoptosis is controversial, In th is study, we demonstrate that ionizing radiation (IR) and dexamethason e (Dex) induce apoptosis in multiple myeloma (MM) derived cell lines, as well as in patient cells, IR-induced apoptosis is associated with a ctivation of SAPK/JNK and p38 kinase, in contrast to Dex-induced apopt osis, which is not associated with activation of stress kinases, Moreo ver, Dex-induced apoptosis is associated with a significant decrease i n the activities of mitogen activated protein kinase (MAPK) and p70(S6 K), whereas IR-treatment does not alter the activity of these kinases. Both IR and Dex induce poly (ADP ribose) polymerase (PARP) cleavage, a signature event of apoptosis. Finally, interleukin-6 (IL-6) inhibits Dex-induced apoptosis, downregulation of MAP and p70(S6K) growth kina ses and PARP cleavage; in contrast, IL-6 does not inhibit IR-induced a poptosis, activation of SAPK/JNK, and PARP cleavage, Taken together, o ur findings suggest that SAPK/JNK activation is not required for apopt osis in MM cells, and that there are at least two distinct apoptotic s ignaling pathways: (i) SAPK/JNK-associated, which is induced by IR and unaffected by IL-6; and (ii) SAPK/JNK-independent, which is induced b y Dex, associated with downregulation of MAPK and p70(S6K) and inhibit ed by IL-6.