title: Death of multiple myeloma cells induced by cAMP-signaling involves downregulation of Mcl-1 via the JAK/STAT pathway.
abstract: There is a continuous search for new therapeutic targets for treatment of multiple myeloma (MM). Here we investigated the mechanisms involved in cAMP-induced apoptosis of human MM cells. cAMP-increasing agents rapidly inhibited activation of JAK1 and its substrate STAT3. In line with STAT3 being a regulator of Mcl-1 transcription, the expression of this pro-survival factor was rapidly and selectively reduced. Notably, exogenous interleukin-6 neither prevented the inhibition of JAK1/STAT3 nor the death of MM cells induced by cAMP. Our results suggest that cAMP-mediated killing of MM cells involves inhibition of the JAK/STAT pathway, making the cAMP-pathway a promising target for treatment of MM.
authors: Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, PO Box 1112, Blindern, N-0317 Oslo, Norway.
authors: Virginie
authors: V
authors: Follin-Arbelet
authors: Maria Lyngaas
authors: ML
authors: Torgersen
authors: Elin Hallan
authors: EH
authors: Naderi
authors: Kristine
authors: K
authors: Misund
authors: Anders
authors: A
authors: Sundan
authors: Heidi Kiil
authors: HK
authors: Blomhoff
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D053668:Syndecan-1 / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053668:Syndecan-1; D005576:Colforsin; D000242:Cyclic AMP; C507904:JAK1 protein, human; D053613:Janus Kinase 1