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Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma

Oncogene volume 20, pages 5991–6000 (2001)Cite this article

Abstract

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-3β, 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 p27KIP1 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.

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References

  • Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA . 1996 EMBO J. 15: 6541–6551

  • Berger LC, Hawley TS, Lust JA, Goldman SJ, Hawley RG . 1994 Biochem. Biophys. Res. Commun. 202: 596–605

  • Biggs III WH, Meisenhelder J, Hunter T, Cavenee WK, Arden KC . 1999 Proc. Natl. Acad. Sci. USA 96: 7421–7426

  • Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC . 1998 Science 282: 1318–1324

  • Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R . 1999 Immunity 10: 105–115

  • Chauhan D, Hideshima T, Pandey P, Treon S, Teoh G, Raje N, Rosen S, Krett N, Husson H, Avraham S, Kharbanda S, Anderson KC . 1999 Oncogene 18: 6733–6740

  • Chauhan D, Hideshima T, Rosen S, Reed JC, Kharbanda S, Anderson K . 2001 J. Biol. Chem. 276: 24453–24456

  • Chauhan D, Kharbanda S, Ogata A, Urashima M, Teoh G, Robertson M, Kufe DW, Anderson KC . 1997a Blood 89: 227–234

  • Chauhan D, Pandey P, Hideshima T, Treon S, Raje N, Davies FE, Shima Y, Tai YT, Rosen S, Avraham S, Kharbanda S, Anderson KC . 2000 J. Biol. Chem. 275: 27845–27850

  • Chauhan D, Pandey P, Ogata A, Teoh G, Krett N, Halgren R, Rosen S, Kufe D, Kharbanda S, Anderson KC . 1997b J. Biol. Chem. 272: 29995–29997

  • Chauhan D, Pandey P, Ogata A, Teoh G, Treon S, Urashima M, Kharbanda S, Anderson KC . 1997c Oncogene 15: 837–843

  • Chen R-H, Chang M-C, Su Y-H, Tsai Y-T, Kou M-L . 1999 J. Biol. Chem. 274: 23013–23019

  • Chung TD, Yu JJ, Kong TA, Spiotto MT, Lin JM . 2000 Prostate 42: 1–7

  • Collado M, Medema RH, Garcia-Cao I, Dubuisson MLN, Barradas M, Glassford J, Rivas C, Burgering BMT, Serrano M, Lam EW-F . 2000 J. Biol. Chem. 275: 21960–21968

  • del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G . 1997 Science 278: 687–689

  • Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NSB, Lam EW-F, Burgering BMT, Raajimakers JAM, Lammeres J-WJ, Koenderman L, Coffer PJ . 2000 Mol. Cell. Biol. 20: 9138–9148

  • Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Seagal RA, Kaplan DR, Greenberg ME . 1997 Science 275: 661–665

  • Ferlin M, Noraz N, Hertogh C, Brochier J, Taylor N, Klein B . 2000 Brt. J. Hematol. 111: 626–634

  • Franklin RA, McCubrey JA . 2000 Leukemia 14: 2019–2034

  • Ge N-L, Rudikoff S . 2000 Blood 96: 2856–2861

  • Hallek M, Bergsagel PL, Anderson KC . 1998 Blood 91: 3–21

  • Hardin J, MacLeod S, Grigorieva I, Chang R, Barlogie B, Xiao H, Epstein J . 1994 Blood 84: 3063–3070

  • Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai Y-T, Treon S, Lin B, Schlossman RL, Ridhardson P, Muller G, Stirling DI, Anderson KC . 2000a Blood 96: 2943–2950

  • Hideshima T, Chauhan D, Teoh G, Raje N, Treon SP, Tai Y-T, Shima Y, Anderson KC . 2000b Clin. Cancer Res. 6: 1180–1189

  • Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC . 2001 Cancer Res. 61: 3071–3076

  • Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto A, Kishimoto T . 1988 Nature 332: 83–85

  • Kennedy SG, Kandel ES, Cross TK, Hay N . 1999 Mol. Cell. Biol. 88: 5800–5810

  • Klein B, Zhang XG, Jourdan M, Content J, Houssiau F, Aarden L, Piechaczyk M, Bataille R . 1989 Blood 73: 517–526

  • Klein B, Zhang XG, Lu ZY, Bataille R . 1995 Blood 85: 863–872

  • Kohn AD, Takeuchi F, Roth RA . 1996 J. Biol. Chem. 271: 21920–21926

  • Lichtenstein A, Tu Y, Fady C, Vescio R, Berenson J . 1995 Cell. Immunol. 162: 248–255

  • Medema RH, Kops GJ, Bos JL, Burgering BM . 2000 Nature 404: 782–787

  • Mendez R, Myers MG, White MF, Rhoads RE . 1996 Mol. Cell. Biol. 16: 2857–2864

  • Mitsuuchi Y, Johnson SW, Selvakumaran M, Williams SJ, Hamilton TC, Testa JR . 2000 Cancer Res. 60: 5390–5394

  • Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M, Sellers WR . 2000 Mol. Cell. Biol. 20: 8969–8982

  • Nishimoto N, Ogata A, Shima Y, Tani Y, Ogawa H, Nakagawa M, Sugiyama H, Yoshizaki K, Kishimoto T . 1994 J. Exp. Med. 179: 1343–1347

  • Ogata A, Chauhan D, Teoh G, Treon SP, Urashima M, Schlossman RL, Anderson KC . 1997 J. Immunol. 159: 2212–2221

  • Ogawa M, Nishiura T, Oritani K, Yoshida H, Yoshimura M, Okajima Y, Ishikawa J, Hashimoto K, Matsumura I, Tomiyama Y, Matsuzawa Y . 2000 Cancer Res. 60: 4262–4269

  • Oh H, Fujio Y, Kunisada K, Hirota H, Matsui H, Kishimoto T, Yamauchi-Takihara K . 1998 J. Biol. Chem. 273: 9703–9710

  • Pap M, Cooper GM . 1998 J. Biol. Chem. 273: 19929–19932

  • Qiu Y, Robinson D, Pretlow TG, Kung H-J . 1998 Proc. Natl. Acad. Sci. USA 95: 3644–3649

  • Rena G, Guo S, Cichy SC, Unterman TG, Cohen P . 1999 J. Biol. Chem. 274: 17179–17183

  • Rommel C, Brian A, Clarke A, Zimmermann S, Nunez G, Rossman R, Reid K, Moelling K, Yancopoulos GD, Glass DJ . 1999 Science 286: 1738–1741

  • Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT . 1998 Science 279: 710–714

  • Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT . 1997 Science 277: 567–570

  • Tu Y, Gardner A, Lichtenstein A . 2000 Cancer Res. 60: 6763–6770

  • Xu FH, Sharma S, Gardner A, Tu Y, Raitano A, Sawyers C, Lichtenstein A . 1998 Blood 92: 241–251

  • Yart A, Laffargue M, Mayeux P, Chretien S, Peres C, Tonks N, Roche S, Payrastre B, Chap H, Raynal P . 2001 J. Biol. Chem. 276: 8856–8864

  • Zhou H, Li X-M, Meinkoth J, Pittman RN . 2000 J. Cell. Biol. 151: 483–494

  • Zimmermann S, Moelling K . 1999 Science 286: 1741–1744

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Acknowledgements

Supported by National Institutes of Health Grants RO-1 50947 and PO-1 78378, and Multiple Myeloma Research Foundation Senior Research Award (D Chauhan) as well as the Doris Duke Distinguished Clinical Research Scientist Award (KC Anderson).

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Authors and Affiliations

  1. Department of Adult Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA 02115, Massachusetts, USA

    Teru Hideshima, Noriaki Nakamura, Dharminder Chauhan & Kenneth C Anderson

  2. Department of Medicine, Harvard Medical School, Boston, MA 02115, Massachusetts, USA

    Teru Hideshima, Noriaki Nakamura, Dharminder Chauhan & Kenneth C Anderson

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  1. Teru Hideshima
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  2. Noriaki Nakamura
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Correspondence to Kenneth C Anderson.

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Hideshima, T., Nakamura, N., Chauhan, D. et al. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 20, 5991–6000 (2001). https://doi.org/10.1038/sj.onc.1204833

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