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2-Methoxyestradiol-induced apoptosis in human leukemia cells proceeds through a reactive oxygen species and Akt-dependent process

Oncogene volume 24, pages 3797–3809 (2005)Cite this article

Abstract

The effects of 2-Methoxyestradiol (2ME)-induced apoptosis was examined in human leukemia cells (U937 and Jurkat) in relation to mitochondrial injury, oxidative damage and perturbations in signaling pathways. 2ME induced apoptosis in these cells in a dose-dependent manner associated with release of mitochondrial proteins (cytochrome c, AIF), generation of reactive oxygen species (ROS), downregulation of Mcl-1 and XIAP and inactivation (dephosphorylation) of Akt accompanied by activation of JNK. In these cells, enforced activation of Akt by a constitutively active myristolated Akt construct prevented 2ME-mediated mitochondrial injury, XIAP and Mcl-1 downregulation, JNK activation and apoptosis, but not ROS generation. Conversely, 2ME lethality was potentiated by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Furthermore, in U937 cells, the hydrogen peroxide scavenger catalase and a superoxide dismutase (SOD) mimetic, TBAP, blocked these events, as well as Akt inactivation. Interruption of the JNK pathway by pharmacologic or genetic (e.g. siRNA) means attenuated 2ME-induced mitochondrial injury, XIAP and Mcl-1 downregulation and apoptosis. Collectively, these findings suggest a hierarchical model of 2ME-related apoptosis induction in human leukemia cells in which 2ME-induced oxidative injury represents a primary event resulting in Akt inactivation, leading, in turn, to JNK activation and culminating in XIAP and Mcl-1 downregulation, mitochondrial injury and apoptosis. They also suggest that in human leukemia cells, the Akt pathway plays a critical role in mediating the response to oxidative stress induced by 2ME.

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References

  • Adler V, Yin Z, Tew KD and Ronai Z . (1999). Oncogene, 18, 6104–6111.

  • Bae J, Donigian JR and Hsueh AJ . (2003). J. Biol. Chem., 278, 5195–5204.

  • Basu S and Kolesnick R . (1998). Oncogene, 17, 3277–3285.

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME . (1999). Cell, 96, 857–868.

  • Bu S, Blaukat A, Fu X, Heldin NE and Landstrom M . (2002). FEBS Lett., 531, 141–151.

  • Cantley LC and Neel BG . (1999). Proc. Natl. Acad. Sci. USA, 96, 4240–4245.

  • Curnock AP and Knox KA . (1998). Cell Immunol., 187, 77–87.

  • Datta SR, Brunet A and Greenberg ME . (1999). Genes Dev., 13, 2905–2927.

  • Deora AA, Win T, Vanhaesebroeck B and Lander HM . (1998). J. Biol. Chem., 273, 29923–29928.

  • Djavaheri-Mergny M, Wietzerbin J and Besancon F . (2003). Oncogene, 22, 2558–2567.

  • Faulkner KM, Liochev SI and Fridovich I . (1994). J. Biol. Chem., 269, 23471–23476.

  • Franke TF, Hornik CP, Segev L, Shostak GA and Sugimoto C . (2003). Oncogene, 22, 8983–8998.

  • Fridovich I . (1999). Ann. NY Acad. Sci., 893, 13–18.

  • Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, Wang HG, Atadja P and Bhalla K . (2003). Mol. Cancer Ther., 2, 971–984.

  • Gao N, Ding M, Zheng JZ, Zhang Z, Leonard SS, Liu KJ, Shi X and Jiang BH . (2002). J. Biol. Chem., 277, 31963–31971.

  • Harris TK . (2003). IUBMB Life, 55, 117–126.

  • Hei TK, Liu SX and Waldren C . (1998). Proc. Natl. Acad. Sci. USA, 95, 8103–8107.

  • Holgado-Madruga M and Wong AJ . (2003). Mol. Cell. Biol., 23, 4471–4484.

  • Huang P, Feng L, Oldham EA, Keating MJ and Plunkett W . (2000). Nature, 407, 390–395.

  • Hughes RA, Harris T, Altmann E, Mcallister D, Vlahos R, Robertson A, Cushman M, Wang Z and Stewart AG . (2002). Mol. Pharmacol., 61, 1053–1069.

  • Ikeyama S, Kokkonen G, Shack S, Wang XT and Holbrook NJ . (2002). FASEB J., 16, 114–116.

  • Johnson GL and Lapadat R . (2002). Science, 298, 1911–1912.

  • Kandel ES, Skeen J, Majewski N, Di Cristofano A, Pandolfi PP, Feliciano CS, Gartel A and Hay N . (2002). Mol. Cell. Biol., 22, 7831–7841.

  • Kausalya S, Somogyi R, Orlofsky A and Prystowsky MB . (2001). J. Immunol., 166, 4721–4727.

  • Kim AH, Khursigara G, Sun X, Franke TF and Chao MV . (2001). Mol. Cell. Biol., 21, 893–901.

  • Kim YS, Jhon DY and Lee KY . (2004). Exp. Mol. Med., 36, 157–164.

  • Kobayashi S, Yamashita K, Takeoka T, Ohtsuki T, Suzuki Y, Takahashi R, Yamamoto K, Kaufmann SH, Uchiyama T, Sasada M and Takahashi A . (2002). J. Biol. Chem., 277, 33968–33977.

  • Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, Huang TT, Bos JL, Medema RH and Burgering BM . (2002). Nature, 419, 316–321.

  • LaVallee TM, Zhan XH, Herbstritt CJ, Kough EC, Green SJ and Pribluda VS . (2002). Cancer Res., 62, 3691–3697.

  • Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A and Downes CP . (2003). EMBO J., 22, 5501–5510.

  • Li SY, Gomelsky M, Duan J, Zhang Z, Gomelsky L, Zhang X, Epstein PN and Ren J . (2004). J. Biol. Chem., 279, 11244–11252.

  • Lin HL, Liu TY, Wu CW and Chi CW . (2001). Cancer, 92, 500–509.

  • Manning BD and Cantley LC . (2003). Biochem. Soc. Trans., 31, 3–578.

  • Mansat-de Mas V, Bezombes C, Quillet-Mary A, Bettaieb A, D'orgeix AD, Laurent G and Jaffrezou JP . (1999). Mol. Pharmacol., 56, 867–874.

  • Mao JH, To MD, Perez-Losada J, Wu D, Del Rosario R and Balmain A . (2004). Genes Dev., 18, 1800–1805.

  • Martindale JL and Holbrook NJ . (2002). J. Cell Physiol., 192, 1–15.

  • Martucci CP and Fishman J . (1993). Pharmacol. Ther., 57, 237–257.

  • Mildner M, Eckhart L, Lengauer B and Tschachler E . (2002). J. Biol. Chem., 277, 14146–14152.

  • Minutoli L, Altavilla D, Marini H, Passaniti M, Bitto A, Seminara P, Venuti FS, Famulari C, Macri A, Versaci A and Squadrito F . (2004). Life Sci., 75, 2853–2866.

  • Mitsiades CS, Mitsiades N and Koutsilieris M . (2004). Curr. Cancer Drug Targets, 4, 235–256.

  • Mockridge JW, Benton EC, Andreeva LV, Latchman DS, Marber MS and Heads RJ . (2000). Biochem. Biophys. Res. Commun., 273, 322–327.

  • Mooberry SL . (2003). Drug Resist. Updates, 6, 355–361.

  • Ozaki M, Haga S, Zhang HQ, Irani K and Suzuki S . (2003). Cell Death Differ., 10, 508–515.

  • Paez J and Sellers WR . (2003). Cancer Treat Res., 115, 145–167.

  • Pei ZM, Murata Y, Benning G, Thomine S, Klusener B, Allen GJ, Grill E and Schroeder JI . (2000). Nature, 406, 731–734.

  • Pene F, Claessens YE, Muller O, Viguie F, Mayeux P, Dreyfus F, Lacombe C and Bouscary D . (2002). Oncogene, 21, 6587–6597.

  • Persad S, Attwell S, Gray V, Delcommenne M, Troussard A, Sanghera J and Dedhar S . (2000). Proc. Natl. Acad. Sci. USA, 97, 3207–3212.

  • Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, Calabretta B and Baserga R . (1999). Mol. Cell. Biol., 19, 7203–7215.

  • Qanungo S, Basu A, Das M and Haldar S . (2002). Oncogene, 21, 4149–4157.

  • Raftopoulou M, Etienne-Manneville S, Self A, Nicholls S and Hall A . (2004). Science, 303, 1179–1181.

  • Rahmani M, Reese E, Dai Y, Bauer C, Payne SG, Dent P, Spiegel S and Grant S . (2005). Cancer Res., 65, 2422–2432.

  • Rahmani M, Yu C, Reese E, Ahmed W, Hirsch K, Dent P and Grant S . (2003). Oncogene, 22, 6231–6242.

  • Reddy P, Maeda Y, Hotary K, Liu C, Reznikov LL, Dinarello CA and Ferrara JL . (2004). Proc. Natl. Acad. Sci. USA, 101, 3921–3926.

  • Rego AC and Oliveira CR . (2003). Neurochem. Res., 28, 1563–1574.

  • Rosato RR, Almenara JA and Grant S . (2003). Cancer Res., 63, 3637–3645.

  • Sawada M, Nakashima S, Kiyono T, Nakagawa M, Yamada J, Yamakawa H, Banno Y, Shinoda J, Nishimura Y, Nozawa Y and Sakai N . (2001). Oncogene, 20, 1368–1378.

  • Shan X, Czar MJ, Bunnell SC, Liu P, Liu Y, Schwartzberg PL and Wange RL . (2000). Mol. Cell. Biol., 20, 6945–6957.

  • Shimada K, Nakamura M, Ishida E, Kishi M, Matsuyoshi S and Konishi N . (2004). Mol. Carcinog., 39, 1–9.

  • Tinley TL, Leal RM, Randall-Hlubek DA, Cessac JW, Wilkens LR, Rao PN and Mooberry SL . (2003). Cancer Res., 63, 1538–1549.

  • Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA and Davis RJ . (2000). Science, 288, 870–874.

  • Wang X, McCullough KD, Franke TF and Holbrook NJ . (2000). J. Biol. Chem., 275, 14624–14631.

  • Yang JY and Widmann C . (2002). J. Biol. Chem., 277, 14641–14646.

  • Yu C, Rahmani M, Almenara J, Sausville EA, Dent P and Grant S . (2004). Oncogene, 23, 1364–1376.

  • Zhang R, Al-Lamki R, Bai L, Streb JW, Miano JM, Bradley J and Min W . (2004). Circ. Res., 94, 1483–1491.

  • Zhao S, Konopleva M, Cabreira-Hansen M, Xie Z, Hu W, Milella M, Estrov Z, Mills G and Andreeff M . (2004). Leukemia, 18, 267–275.

  • Zhou DC, Kim SH, Ding W, Schultz C, Warrell Jr RP and Gallagher RE . (2002). Blood, 99, 1356–1363.

  • Zoubine MN, Weston AP, Johnson DC, Campbell DR and Banerjee SK . (1999). Int. J. Oncol., 15, 639–646.

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Acknowledgements

This work was supported by awards CA 63753, CA 100866 and CA 93738 from the NIH, award 6045-03 from the Leukemia and Lymphoma Society of America and award DAMD-17-03-1-0209 from the Department of Defense.

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Authors and Affiliations

  1. Department of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, 23298, USA

    Ning Gao, Mohamed Rahmani, Paul Dent & Steven Grant

  2. Department of Radiation Oncology, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, 23298, USA

    Paul Dent

  3. Department of Biochemistry, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, 23298, USA

    Steven Grant

  4. Department of Pharmacology, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, 23298, USA

    Paul Dent & Steven Grant

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Gao, N., Rahmani, M., Dent, P. et al. 2-Methoxyestradiol-induced apoptosis in human leukemia cells proceeds through a reactive oxygen species and Akt-dependent process. Oncogene 24, 3797–3809 (2005). https://doi.org/10.1038/sj.onc.1208530

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