title: Nuclear factor-kappaB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis.
abstract: Chemoresistance is a major problem in the treatment of patients with multiple myeloma (MM). Because of the central role of the nuclear transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) in chemoresistance, cell survival, and proliferation, we investigated whether MM cells derived from patients express activated NF-kappaB and STAT3 and if their suppression induces apoptosis. We assayed CD138+ cells from the bone marrow of 22 MM patients and checked for the activated forms of NF-kappaB and STAT3 by immunocytochemistry. We found that MM cells from all the patients expressed the activated forms of NF-kappaB and STAT3 but to a variable degree (NF-kappaB: low, 3 of 22; moderate, 5 of 22; or high, 14 of 22; STAT3: none, 1 of 22; low, 3 of 22; moderate, 5 of 22; or high, 14 of 22). Constitutive activation of NF-kappaB was in some cases also independently confirmed by electrophoretic mobility gel shift assay. In contrast to MM patients, activated forms of NF-kappaB and STAT3 were absent in cells from healthy individuals. Suppression of NF-kappaB and STAT3 activation in MM cells by ex vivo treatment with curcumin (diferuloylmethane) resulted in a decrease in adhesion to bone marrow stromal cells, cytokine secretion, and in the viability of cells. When compared with curcumin, dexamethasone was less effective in suppression of NF-kappaB activation and induction of apoptosis in myeloma cells. Overall, our results indicate that fresh cells from MM patients express constitutively active NF-kappaB and STAT3, and suppression of these transcription factors inhibits the survival of the cells.
authors.affiliation: Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: Alok C
authors.initials: AC
authors.lastname: Bharti
authors.forename: Shishir
authors.initials: S
authors.lastname: Shishodia
authors.forename: James M
authors.initials: JM
authors.lastname: Reuben
authors.forename: Donna
authors.initials: D
authors.lastname: Weber
authors.forename: Raymond
authors.initials: R
authors.lastname: Alexanian
authors.forename: Saroj
authors.initials: S
authors.lastname: Raj-Vadhan
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D050796:STAT3 Transcription Factor; D053668:Syndecan-1; D053667:Syndecans; D015534:Trans-Activators / Q000378:metabolism*; D051996:Transcription Factor RelA
chemical_list: D004268:DNA-Binding Proteins; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011509:Proteoglycans; C508241:SDC1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053668:Syndecan-1; D053667:Syndecans; D015534:Trans-Activators; D051996:Transcription Factor RelA; D003907:Dexamethasone; D003474:Curcumin