title: Role for interleukin-6 and insulin-like growth factor-I via PI3-K/Akt pathway in the proliferation of CD56- and CD56+ multiple myeloma cells.
abstract: OBJECTIVE
  Several studies including ours have suggested that lack of CD56 in multiple myeloma (MM) defines a unique patient subset with poorer prognosis. However, the mechanism underlying this aggressive behavior of CD56(-) MM has not been well elucidated. Interleukin-6 (IL-6) or insulin-like growth factor I (IGF-I) induce proliferation of MM cells. In this study, we report about the relationship between CD56 expression and responsiveness to these cytokines.
  
  
  METHODS
  We sorted out both CD56(-) and CD56(+) fractions from MM cell lines such as KMS-21-BM and U-266, and investigated their different responsiveness to IL-6 or IGF-I. Furthermore, we compared the effects of these cytokines on the regulation of cell-cycle distribution between CD56(-) and CD56(+) cells.
  
  
  RESULTS
  Although CD56(-) cells in both KMS-21-BM and U-266 cells responded significantly to IL-6, CD56(+) cells did not. Ki-67(+) cells in the CD56(-) cells were significantly increased by IL-6. Western blotting showed that IL-6 phosphorylated Akt, and upregulated and downregulated the level of cyclin D1 and p27 protein in the CD56(-) KMS-21-BM cells, respectively. LY-294002 completely blocked these effects of IL-6. On the other hand, Ki-67(+) cells in the CD56(+) cells did not respond to IL-6. Anti-IGF-I mAb significantly reduced Ki-67(+) cells only in the CD56(+) cells. IGF-I phosphorylated Akt and upregulated cyclin D1 in the CD56(+) KMS-21-BM cells, which was completely blocked by LY294002.
  
  
  CONCLUSIONS
  These results suggest that CD56(-) and CD56(+) MM cells could be stimulated by IL-6 and IGF-I, respectively, via PI3-K/Akt pathway, and provide useful information for anticytokine therapies.
authors.affiliation: Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan. sahara@hama-med.ac.jp
authors.forename: Naohi
authors.initials: N
authors.lastname: Sahara
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takeshita
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ono
authors.forename: Yuya
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Miki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shigeno
authors.forename: Satoki
authors.initials: S
authors.lastname: Nakamura
authors.forename: Kaori
authors.initials: K
authors.lastname: Shinjo
authors.forename: Kensuke
authors.initials: K
authors.lastname: Naito
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Shibata
authors.forename: Takemi
authors.initials: T
authors.lastname: Otsuki
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hayashi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohnishi
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D019002:CD56 Antigen; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D004791:Enzyme Inhibitors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D019394:Ki-67 Antigen; D009025:Morpholines / Q000494:pharmacology; D009101:Multiple Myeloma / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D019002:CD56 Antigen; D002867:Chromones; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D019394:Ki-67 Antigen; D009025:Morpholines; D019938:Cyclin D1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt