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An inhibitory function for JNK in the regulation of IGF-I signaling in breast cancer

Oncogene volume 22, pages 602–614 (2003)Cite this article

Abstract

Insulin-like growth factor-I receptor (IGF-IR) is frequently overexpressed in a variety of cancer types. Since many breast tumors and cancer cell lines overexpress IGF-IR, we tested IGF-I effects on chemotherapy-treated breast cancer cells. IGF-I protects from chemotherapy-induced apoptosis, suggesting that overlapping signaling pathways modulate IGF-I and chemotherapy treatment outcomes. Taxol and other chemotherapy drugs induce c-Jun N-terminal kinase (JNK), a kinase that conveys cellular stress and death signals. Notably, in this paper we show that IGF-I alone induces a potent JNK response and this activity is reversed by inhibition of phosphatidylinositol 3-kinase (PI 3-kinase) with LY294002 in MCF-7 but not T47D cells. Cotreatment of cells with chemotherapy and IGF-I leads to additive JNK responses. Using cells overexpressing Akt, we confirm that IGF-I-mediated survival is Akt dependent. In contrast, overexpression of JNK significantly enhances Taxol-induced apoptosis and inhibits IGF-I survival effects. Further, JNK attenuates anchorage-independent growth of MCF-7 cells. The inhibitory effect of JNK appears to be mediated by serine phosphorylation of IRS-1 (insulin receptor substrate) since both Taxol and IGF-I treatment enhanced Ser312 IRS-1 phosphorylation, while LY294002 blocked IGF-I-mediated phosphorylation. Taken together, these data provide a mechanism whereby stress or growth factors activate JNK to reduce proliferation and/or survival in breast cancer cells.

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References

  • Aguirre V, Werner ED, Giraud J, Lee YH, Schoelson SE and White MF . (2002). J. Biol. Chem., 277, 1531–1537.

  • Alblas J, Slager-Davidov R, Steenbergh PH, Sussenbach JS and van der Burg B . (1998). Oncogene, 16, 131–139.

  • Bost F, McKay R, Dean N and Mercola D . (1997). J. Biol. Chem., 272, 33422–33429.

  • 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.

  • Butler AA, Blakesley VA, Tsokos M, Pouliki V, Wood TL and LeRoith D . (1998). Cancer Res., 58, 3021–3027.

  • Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S and Reed JC . (1998). Science, 282, 1318–1321.

  • Chen Y-R, Meyer CF and Tna T-H . (1996). J. Biol. Chem., 271, 631–634.

  • Chen N, Nomura M, She QB, Ma WY, Bode AM, Wang L, Flavell RA and Dong Z . (2001). Cancer Res., 61, 3908–3912.

  • Cuenda A, Cohen P, Buee-Scherrer V and Goedert M . (1997). EMBO J., 16, 295–305.

  • Cullen KJ, Yee D, Sly WS, Perdue J, Hampton B, Lippman ME and Rosen N . (1990). Cancer Res., 50, 48–53.

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME . (1997). Cell, 91, 231–241.

  • De Fea K and Roth RA . (1997). J. Biol. Chem., 272, 31400–31406.

  • Desbois-Mouthon C, Blivet-Van Eggelpoel M-J, Auclair M, Cherqui G, Capeau J and Caron M . (1998). Biochem. Biophys. Res. Commun., 243, 765–770.

  • Dunn SE, Ehrlich M, Sharp NJH, Solomon G, Hawkins R, Baserga R and Barrett JC . (1998). Cancer Res., 58, 3353–3361.

  • Fanger GR, Lassignal Johnson N and Johnson GL . (1997). EMBO J., 16, 4961–4972.

  • Franke TF, Yang S-I, Chan TO, Datta K, Kaziauskas A, Morrison DK, Kaplan DR and Tsichlis PN . (1995). Cell, 81, 727–736.

  • Fuchs SY, Fried VA and Ronai Z . (1998). Oncogene, 17, 1483–1490.

  • Goedert M, Cuenda A, Craxton M, Jakes R and Cohen P . (1997). EMBO J., 16, 3563–3571.

  • Gooch JL, Van Den Berg CL and Yee D . (1999). Breast Cancer Res. Treatment, 56, 1–10.

  • Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B and Davis RJ . (1996). EMBO J., 15, 2760–2770.

  • Hemi R, Paz K, Wertheim N, Karasik A, Zick Y and Kanety H . (2002). J. Biol. Chem., 277, 8961–8969.

  • Hermanto U, Zong CS and Wang LH . (2000). Cell Growth Differ., 12, 655–664.

  • Hibi M, Lin A, Smeal T, Minden A and Karin M . (1993). Genes Dev., 7, 2135–2148.

  • Kennedy SG, Wagner AJ, Conzen SD, Jordan J, Bellacosa A, Tsichlis PN and Hay N . (1997). Genes Dev., 11, 701–713.

  • Kyriakas JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J and Woodget JR . (1994). Nature (London), 369, 156–159.

  • Lee AV, Gooch JL, Oesterrich S, Guler RL and Yee D . (2000). Mol. Cell. Biol., 20, 1489–1496.

  • Logan SK, Falasca M, Hu P and Schlessinger J . (1997). Mol. Cell. Biol., 17, 5784–5790

  • Lopez-Ilasaca M, Li W, Uren A, Yu J, Kazlauskas A, Gutkind JS and Heideran MA . (1997). Biochem. Biophys. Res. Commun., 232, 273–277.

  • Miller BS, Shankavaram UT, Horney MJ, Gore ACS, Kurtz DT and Rosenzweig SA . (1996). Biochemistry, 35, 8769–8775.

  • Minden A and Karin M . (1997). Biochim. Biophys. Acta, 1333, F85–F104.

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

  • Monno S, Newman MV, Cook M and Lowe W . (2000). Endocrinology, 141, 544–550.

  • Okubo Y, Blakesley VA, Stannard B, Gutkind S and Le Roith D . (1998). J. Biol. Chem., 273, 25961–25966.

  • Paz K, Liu Y-F, Shorer H, Hemi R, LeRoith D, Quan M, Kanety H, Seger R and Zick Y . (1999). J. Biol. Chem., 274, 28816–28822.

  • Peyrat JP, Bonneterre J, Jammes H, Beuscart R, Hecquet B, Djiane J, Lefebvre J and Demaille A . (1990). J. Steroid Biochem. Mol. Biol, 37, 823–827.

  • Potapova O, Gorospe M, Dougherty RH, Dean NM, Gaarde WA and Holbrook NJ . (2000). Mol. Cell. Biol., 20, 1713–1722.

  • Potapova O, Haghighi A, Bost F, Liu C, Birrer MJ, Gjerset R and Mercolas D . (1995). J. Biol. Chem., 272, 14041–14044.

  • Resnik JL, Reichart DB, Huey K, Webster NJG and Seely BL . (1998). Cancer Res., 58, 1159–1164.

  • Rosette C and Karin M . (1996). Science, 274, 1194–1197.

  • Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A, Dunaif A and White MF . (2001). The Journal of Clinical Investigation 107, 181–189.

  • She QB, Chen N, Bode AM, Flavell RA and Dong Z . (2002). Cancer Res., 62, 1343–1348.

  • Singer C, Rasmussen A, Smith HS, Lippman ME, Lynch HT and Cullen KJ . (1995). Cancer Res., 55, 2448–2454.

  • Sluss, HK ., Barrett, T ., Derijard, B and Davis, R.J . (1994). Mol Cell. Biol., 14, 8376–8384.

  • Smith DB and Johnson KS . (1988). Gene, 67, 31–40.

  • Van Den Berg CL, Cox GN, Stroh CA, Hilsenbeck SG, Weng C, McDermott MJ, Pratt D and Yee D . (1997). Eur. J. Cancer, 33, 1108–1113.

  • Wang T-H, Eang H-S, Ichijo H, Giannakakou P, Foster JS, Fojo T and Wimalasena J . (1998). J. Biol. Chem., 273, 4928–3936.

  • Westwick JK, Weitzel C, Minden A, Karin M and Brenner DA . (1994). J. Biol. Chem. 26396–26401.

  • Whitmarsh AJ, Shore P, Sahrrocks AD and Davis RJ . (1995). Science, 269, 403–407.

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Acknowledgements

This work was supported in part by the Public Health Service Grant CA89288A awarded by the National Cancer Institute, Susan G Komen Foundation, Avon Breast Cancer Foundation and United States Army Medical Research, and Command Grant DAMD17-99-1-9142 (to CLVDB). The content of this information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. We thank Heather Ferguson for a thoughtful and critical review of this manuscript.

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Authors and Affiliations

  1. Department of Biological Chemistry, University of California, Davis, 95616-8655, CA, USA

    Cindy L Mamay

  2. School of Pharmacy, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Campus Box C238, Denver, 80262, CO, USA

    Amy M Mingo-Sion, Doug M Wolf, Marion D Molina & Carla L Van Den Berg

  3. Department of Obstetrics and Gynecology, School of Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Campus Box B198, Denver, 80262, CO, USA

    Doug M Wolf

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  1. Cindy L Mamay
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Correspondence to Carla L Van Den Berg.

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Mamay, C., Mingo-Sion, A., Wolf, D. et al. An inhibitory function for JNK in the regulation of IGF-I signaling in breast cancer. Oncogene 22, 602–614 (2003). https://doi.org/10.1038/sj.onc.1206186

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