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Molecules and Cells

, Volume 32, Issue 1, pp 107–111 | Cite as

PI3-Kinase/p38 kinase-dependent E2F1 activation is critical for pin1 induction in tamoxifen-resistant breast cancer cells

  • Kwang Youl Lee
  • Jeong Woon Lee
  • Hyun Jeong Nam
  • Jeong-Hyun Shim
  • Youngsup Song
  • Keon Wook KangEmail author
Article

Abstract

Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. We have shown that Pin1, a peptidyl prolyl isomerase, is consistently overexpressed in TAM-resistant MCF-7 cells (TAMR-MCF-7 cells) and plays a key role in the enhanced angiogenic potential of TAMR-MCF-7 cells. In the present study, we focused on signaling pathways for Pin1 up-regulation in TAMR-MCF-7 cells. Relative to MCF-7 cells, Pin1 gene transcription and E2 transcription factor1 (E2F1) expression were enhanced in TAMR-MCF-7 cells. E2F1 siRNA significantly reduced both the protein expression and the promoter transcriptional activity of Pin1. Activities of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK) and p38 kinase were all higher in TAMR-MCF-7 cells than in control MCF-7 cells and the enhanced Pin1 and E2F1 expression in TAMR-MCF-7 cells was reversed by inhibition of PI3K or p38 kinase. Moreover, the higher production of vascular endothelial growth factor (VEGF) in TAMR-MCF-7 cells was significantly diminished by suppression of PI3K or p38 kinase. These results suggest that Pin1 overexpression and subsequent VEGF production in TAMR-MCF-7 cells are mediated through PI3-kinase or p38 kinase-dependent E2F1 activation.

Keywords

E2F1 p38 kinase PI3-kinase Pin1 tamoxifen-resistant breast cancer VEGF 

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References

  1. Ali, S., and Coombes, R.C. (2002). Endocrine-responsive breast cancer and strategies for combating resistance. Nat. Rev. Cancer 2, 101–112.PubMedCrossRefGoogle Scholar
  2. Bao, L., Sauter, G., Sowadski, J., Lu, K.P., and Wang, D. (2004). Prevalent overexpression of prolyl isomerase Pin1 in human cancers. Am. J. Pathol. 164, 1727–1737.PubMedCrossRefGoogle Scholar
  3. Bayer, E., Goettsch, S., Mueller, J.W., Griewel, B., Guiberman, E., Mayr, L.M., and Bayer, P. (2003). Structural analysis of the mitotic regulator hPin1 in solution: insights into domain architecture and substrate binding. J. Biol. Chem. 278, 26183–26193.PubMedCrossRefGoogle Scholar
  4. Bracken, A.P., Ciro, M., Cocito, A., and Helin, K. (2004). E2F target genes: unraveling the biology. Trends Biochem. Sci. 29, 409–417.PubMedCrossRefGoogle Scholar
  5. Chaussepied, M., and Ginsberg, D. (2004). Transcriptional regulation of AKT activation by E2F. Mol. Cell 16, 831–837.PubMedCrossRefGoogle Scholar
  6. Choi, H.K., Yang, J.W., Roh, S.H., Han, C.Y., and Kang, K.W. (2007). Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells. Endocr. Relat. Cancer 14, 293–303.PubMedCrossRefGoogle Scholar
  7. Clemons, M., Danson, S., and Howell, A. (2002). Tamoxifen (’Nolvadex’): a review, Cancer Treat. Rev. 28, 165–180.Google Scholar
  8. Finn, G., and Lu, K.P. (2008). Phosphorylation-specific prolyl isomerase Pin1 as a new diagnostic and therapeutic target for cancer. Curr. Cancer Drug Targets 8, 223–229.PubMedCrossRefGoogle Scholar
  9. Hershko, T., Korotayev, K., Polager, S., and Ginsberg, D. (2006). E2F1 modulates p38 MAPK phosphorylation via transcriptional regulation of ASK1 and Wip1. J. Biol. Chem. 281, 31309–31316.PubMedCrossRefGoogle Scholar
  10. Johnson, D.G., and Degregori, J. (2006). Putting the oncogenic and tumor suppressive activities of E2F into context. Curr. Mol. Med. 6, 731–738.PubMedGoogle Scholar
  11. Kim, M.R., Choi, H.S., Heo, T.H., Hwang, S.W., and Kang, K.W. (2008). Induction of vascular endothelial growth factor by peptidyl-prolyl isomerase Pin1 in breast cancer cells. Biochem. Biophys. Res. Commun. 369, 547–553.PubMedCrossRefGoogle Scholar
  12. Kim, M.R., Choi, H.S., Yang, J.W., Park, B.C., Kim, J.A., and Kang, K.W. (2009a). Enhancement of vascular endothelial growth factor-mediated angiogenesis in tamoxifen-resistant breast cancer cells: role of Pin1 overexpression. Mol. Cancer Ther. 8, 2163–2171.PubMedCrossRefGoogle Scholar
  13. Kim, M.R., Choi, H.K., Cho, K.B., Kim, H.S., and Kang, K.W. (2009b). Involvement of Pin1 induction in epithelial-mesenchymal transition of tamoxifen-resistant breast cancer cells. Cancer Sci. 100, 1834–1841.PubMedCrossRefGoogle Scholar
  14. Lee, N.Y., Choi, H.K., Shim, J.H., Kang, K.W., Dong, Z., and Choi, H.S. (2009). The prolyl isomerase Pin1 interacts with a ribosomal protein S6 kinase to enhance insulin-induced AP-1 activity and cellular transformation. Carcinogenesis 30, 671–681.PubMedCrossRefGoogle Scholar
  15. Lu, K.P. (2004). Pinning down cell signaling, cancer and Alzheimer’s disease. Trends Biochem. Sci. 29, 200–209.PubMedCrossRefGoogle Scholar
  16. Pang, R., Lee, T.K., Poon, R.T., Fan, S.T., Wong, K.B., Kwong, Y.L., and Tse, E. (2007). Pin1 interacts with a specific serineproline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis. Gastroenterology 132, 1088–1103.PubMedCrossRefGoogle Scholar
  17. Petrangeli, E., Lubrano, C., Ortolani, F., Ravenna, L., Vacca, A., Sciacchitano, S., Frati, L., and Gulino, A. (1994). Estrogen receptors: new perspectives in breast cancer management. J. Steroid Biochem. Mol. Biol. 49, 327–331.PubMedCrossRefGoogle Scholar
  18. Pintus, G., Tadolini, B., Posadino, A.M., Sanna, B., Debidda, M., Carru, C., Deiana, L., and Ventura, C. (2003). PKC/Raf/MEK/ERK signaling pathway modulates native-LDL-induced E2F-1 gene expression and endothelial cell proliferation. Cardiovasc. Res. 59, 934–944.PubMedCrossRefGoogle Scholar
  19. Polager, S., and Ginsberg, D. (2008). E2F-at the crossroads of life and death. Trends Cell Biol. 18, 528–535.PubMedCrossRefGoogle Scholar
  20. Pulikkan, J.A., Dengler, V., Peer Zada, A.A., Kawasaki, A., Geletu, M., Pasalic, Z., Bohlander, S.K., Ryo, A., Tenen, D.G., and Behre, G. (2010). Elevated PIN1 expression by C/EBPalpha-p30 blocks C/EBPalpha-induced granulocytic differentiation through c-Jun in AML. Leukemia 24, 914–923.PubMedCrossRefGoogle Scholar
  21. Reichert, M., Saur, D., Hamacher, R., Schmid, R.M., and Schneider, G. (2007). Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells. Cancer Res. 67, 4149–4156.PubMedCrossRefGoogle Scholar
  22. Ren, B., Cam, H., Takahashi, Y., Volkert, T., Terragni, J., Young, R.A., and Dynlacht, B.D. (2002). E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev. 16, 245–256.PubMedCrossRefGoogle Scholar
  23. Rose, C., Thorpe, S.M., Andersen, K.W., Pedersen, B.V., Mouridsen, H.T., Blichert-Toft, M., and Rasmussen, B.B. (1985). Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values. Lancet 1, 16–19.PubMedCrossRefGoogle Scholar
  24. Ryo, A., Liou, Y.C., Wulf, G., Nakamura, M., Lee, S.W., and Lu, K.P. (2002). PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells. Mol. Cell. Biol. 22, 5281–5295.PubMedCrossRefGoogle Scholar
  25. Shimizu, T., Akiyama, H., Abe, Y., Sasada, H., Sato, E., Miyamoto, A., and Uchida, T. (2006). Expression of Pin1, a peptidyl-prolyl isomerase, in the ovaries of eCG/hCG-treated immature female mice. J. Reprod. Dev. 52, 287–291.PubMedCrossRefGoogle Scholar
  26. Wang, W.H., Hullinger, R.L., and Andrisani, O.M. (2008). Hepatitis B virus X protein via the p38MAPK pathway induces E2F1 release and ATR kinase activation mediating p53 apoptosis. J. Biol. Chem. 283, 25455–25467.PubMedCrossRefGoogle Scholar
  27. Weiwad, M., Küllertz, G., Schutkowski, M., and Fischer, G. (2000). Evidence that the substrate backbone conformation is critical to phosphorylation by p42 MAP kinase. FEBS Lett. 478, 39–42.PubMedCrossRefGoogle Scholar
  28. Wulf, G.M., Ryo, A., Wulf, G.G., Lee, S.W., Niu, T., Petkova, V., and Lu, K.P. (2001). Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1. EMBO J. 20, 3459–3472.PubMedCrossRefGoogle Scholar
  29. Wulf, G., Garg, P., Liou, Y.C., Iglehart, D., and Lu, K.P. (2004). Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis. EMBO J. 23, 3397–3407.PubMedCrossRefGoogle Scholar
  30. You, H., Zheng, H., Murray, S.A., Yu, Q., Uchida, T., Fan, D., and Xiao, Z.X. (2002). IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry. J. Cell. Biochem. 84, 211–216.PubMedCrossRefGoogle Scholar
  31. Zhou, X.Z., Kops, O., Werner, A., Lu, P.J., Shen, M., Stoller, G., Küllertz, G., Stark, M., Fischer, G., and Lu, K.P. (2000). Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins. Mol. Cell 6, 873–883.PubMedCrossRefGoogle Scholar

Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2011

Authors and Affiliations

  • Kwang Youl Lee
    • 2
  • Jeong Woon Lee
    • 1
  • Hyun Jeong Nam
    • 1
  • Jeong-Hyun Shim
    • 3
  • Youngsup Song
    • 4
  • Keon Wook Kang
    • 1
    Email author
  1. 1.Brain Korea 21 Project Team, College of PharmacyChosun UniversityGwangjuKorea
  2. 2.College of PharmacyChonnam National UniversityGwangjuKorea
  3. 3.School of MedicineSoonchunhyang UniversityAsanKorea
  4. 4.The Salk Institute for Biological StudiesLa JollaUSA

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