Multiple signal transduction pathways are involved in G2/M growth arrest and apoptosis induced by the immunomodulator AS101 in multiple myeloma.
The organotellurium compound, AS101, induces G(2)/M growth arrest and apoptosis in multiple myeloma (MM) cell lines. To characterize the mechanism by which AS101 promotes these effects, an antibody microarray analysis was performed, comparing levels of proteins and phosphoproteins in untreated versus AS101-treated mouse 5T33 MM cells. We found that AS101 down-regulated Ilk-1, Cdc25C and phosphorylation of Plk-1 on Thr210, all of which can affect the onset of mitosis or cell survival. In addition, AS101 inhibited the activity of a high molecular weight matrix metalloproteinase complex corresponding to the MMP-9/NGAL complex. Another signaling pathway that was affected by AS101 involves p53 and p65/RelA. Levels of both proteins were elevated upon treatment with AS101. Thus, multiple signaling pathways are involved in the G(2)/M growth arrest and apoptosis induced by AS101 in multiple myeloma, suggesting that if one pathway becomes unresponsive, the therapeutic effect of AS101 might persist through alternative pathways.
Safdié Institute for AIDS and Immunology Research, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Yaniv
Y
Naor
Michal
M
Hayun
Benjamin
B
Sredni
Jeremy
J
Don
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D005030:Ethylenes / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D007155:Immunologic Factors / Q000494:pharmacology*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008970:Molecular Weight; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D040901:Proteomics; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D005030:Ethylenes; D007155:Immunologic Factors; D046912:Multiprotein Complexes; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D020782:Matrix Metalloproteinases