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.
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Ali, S., and Coombes, R.C. (2002). Endocrine-responsive breast cancer and strategies for combating resistance. Nat. Rev. Cancer 2, 101–112.
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.
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.
Bracken, A.P., Ciro, M., Cocito, A., and Helin, K. (2004). E2F target genes: unraveling the biology. Trends Biochem. Sci. 29, 409–417.
Chaussepied, M., and Ginsberg, D. (2004). Transcriptional regulation of AKT activation by E2F. Mol. Cell 16, 831–837.
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.
Clemons, M., Danson, S., and Howell, A. (2002). Tamoxifen (’Nolvadex’): a review, Cancer Treat. Rev. 28, 165–180.
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.
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.
Johnson, D.G., and Degregori, J. (2006). Putting the oncogenic and tumor suppressive activities of E2F into context. Curr. Mol. Med. 6, 731–738.
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.
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.
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.
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.
Lu, K.P. (2004). Pinning down cell signaling, cancer and Alzheimer’s disease. Trends Biochem. Sci. 29, 200–209.
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.
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.
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.
Polager, S., and Ginsberg, D. (2008). E2F-at the crossroads of life and death. Trends Cell Biol. 18, 528–535.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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Lee, K.Y., Lee, J.W., Nam, H.J. et al. PI3-Kinase/p38 kinase-dependent E2F1 activation is critical for pin1 induction in tamoxifen-resistant breast cancer cells. Mol Cells 32, 107–111 (2011). https://doi.org/10.1007/s10059-011-0074-y
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DOI: https://doi.org/10.1007/s10059-011-0074-y