Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma.
Previous studies demonstrate that interleukin-6 (IL-6) mediates growth and survival in human multiple myeloma (MM) cells via the MEK/MAPK and JAK/STAT signaling pathways, respectively. IL-6 also confers protection against Dexamethasone (Dex)-induced apoptosis via activation of protein tyrosine phosphatase (SHP2). In the current study, we characterized IL-6 triggered phophatidylinositol-3 kinase/Akt kinase (PI3-K/Akt) signaling in MM cells. IL-6 induces Akt/PKB phosphorylation in a time and dose dependent manner in MM.1S MM cells. IL-6 also induced phosphorylation of downstream targets of Akt, including Bad, GSK-3beta, and FKHR, confirming Akt activation. Inhibition of Akt activation by the PI3-K inhibitor LY294002 partially blocked IL-6 triggered MEK/MAPK activation and proliferation in MM.1S cells, suggesting cross-talk between PI3-K and MEK signaling. We demonstrate that Dex-induced apoptosis in MM.1S cells is mediated by downstream activation of caspase-9, with resultant caspase-3 cleavage; and conversely, that IL-6 triggers activation of PI3-K and its association with SHP2, inactivates caspase-9, and protects against Dex-induced apoptosis. LY294002 completely abrogates this signaling cascade, further confirming the importance of PI3-K/Akt signaling in conferring the protective effect of IL-6 against Dex-induced apoptosis. Finally, we show that IL-6 triggered PI3-K/Akt signaling in MM.1S cells inactivates forkhead transcriptional factor (FKHR), with related G1/S phase transition, whereas LY294002 blocks this signaling, resulting in upregulation of p27(KIP1) and G1 growth arrest. Our data therefore suggest that PI3-K/Akt signaling mediates growth, survival, and cell cycle regulatory effects of IL-6 in MM.
Hideshima
T
T
Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Nakamura
N
N
Chauhan
D
D
Anderson
K C
KC
D017209:Apoptosis; D053453:Caspase 9; D061945:Caspase Inhibitors; D002453:Cell Cycle; D002867:Chromones / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D009025:Morpholines / Q000494:pharmacology; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D053453:Caspase 9; D061945:Caspase Inhibitors; D002867:Chromones; D003907:Dexamethasone; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; C506433:CASP9 protein, human