Abstract
Cisplatin (CDDP) is an efficient DNA-damaging antitumor agent employed for the treatment of various human cancers. CDDP activates nuclear as well as cytoplasmatic signaling pathways involved in regulation of the cell cycle, damage repair and programmed cell death. Here we report that CDDP also activates a membrane-integrated protein, the epidermal growth factor receptor (EGFR). We show that EGFR is activated in response to CDDP in various types of cells that overexpress the receptor, including transformed human glioma cells and human breast tumor cells. CDDP-induced EGFR activation requires its kinase activity, as it can be blocked by an EGFR kinase inhibitor or by expression of a kinase dead receptor. We also show that CDDP-induced EGFR activation is independent of receptor ligand. CDDP induces the activation of c-Src, and EGFR activation is blocked by Src-family inhibitor PP1, suggesting that Src kinases mediate CDDP-induced EGFR activation. We propose that EGFR activation in response to CDDP is a survival response, since inhibition of EGFR activation enhances CDDP-induced death. These findings show that signals generated by DNA damage can modulate EGFR activity, and argue that interfering with CDDP-induced EGFR activation in tumor cells might be a useful approach to sensitize these cells to genotoxic agents.
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References
Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Tanaka M, Shiojima I, Hiroi Y, Yazaki Y . 1997 J. Clin. Invest. 100: 1813–1821
Benhar M, Dalyot I, Engelberg D, Levitzki A . 2001 Mol. Cell. Biol. 21: 6913–6926
Benhar M, Engelberg D, Levitzki A . 2002 EMBO Rep. 3: 420–425
Biscardi JS, Maa MC, Tice DA, Cox ME, Leu TH, Parsons SJ . 1999 J. Biol. Chem. 274: 8335–8343
Chen K, Vita JA, Berk BC, Keaney Jr JF . 2001 J. Biol. Chem. 276: 16045–16050
Daub H, Wallasch C, Lankenau A, Herrlich A, Ullrich A . 1997 EMBO J. 16: 7032–7044
Deschesnes RG, Huot J, Valerie K, Landry J . 2001 Mol. Biol. Cell. 12: 1569–1582
Fang L, Li G, Liu G, Lee SW, Aaronson SA . 2001 EMBO J. 20: 1931–1939
Gebauer G, Mirakhur B, Nguyen Q, Shore SK, Simpkins H, Dhanasekaran N . 2000 Int. J. Oncol. 16: 321–325
Gibson S, Tu S, Oyer R, Anderson SM, Johnson GL . 1999 J. Biol. Chem. 274: 17612–17618
Haas M, Wang H, Tian J, Xie Z . 2002 J. Biol. Chem. 277: 18694–18702
Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ, Pollok BA, Connelly PA . 1996 J. Biol. Chem. 271: 695–701
Johnson GR, Kannan B, Shoyab M, Stromberg K . 1993 J. Biol. Chem. 268: 2924–2931
Jordan P, Carmo-Fonseca M . 2000 Cell. Mol. Life Sci. 57: 1229–1235
Kartalou M, Essigmann JM . 2001 Mutat. Res. 478: 23–43
Kitagawa D, Tanemura S, Ohata S, Shimizu N, Seo J, Nishitai G, Watanabe T, Nakagawa K, Kishimoto H, Wada T, Tezuka T, Yamamoto T, Nishina H, Katada T . 2001 J. Biol. Chem. 2: 2
Knebel A, Rahmsdorf HJ, Ullrich A, Herrlich P . 1996 EMBO J. 15: 5314–5325
Leu CM, Chang C, Hu C . 2000 Oncogene 19: 1665–1675
Lin RZ, Hu ZW, Chin JH, Hoffman BB . 1997 J. Biol. Chem. 272: 31196–31202
Luttrell LM, Della Rocca GJ, van Biesen T, Luttrell DK, Lefkowitz RJ . 1997 J. Biol. Chem. 272: 4637–4644
Maudsley S, Pierce KL, Zamah AM, Miller WE, Ahn S, Daaka Y, Lefkowitz RJ, Luttrell LM . 2000 J. Biol. Chem. 275: 9572–9580
Miyajima A, Nakashima J, Yoshioka K, Tachibana M, Tazaki H, Murai M . 1997 Br. J. Cancer 76: 206–210
Moro L, Dolce L, Cabodi S, Bergatto E, Erba EB, Smeriglio M, Turco E, Retta SF, Giuffrida MG, Venturino M, Godovac-Zimmermann J, Conti A, Schaefer E, Beguinot L, Tacchetti C, Gaggini P, Silengo L, Tarone G, Defilippi P . 2002 J. Biol. Chem. 277: 9405–9414
Moro L, Venturino M, Bozzo C, Silengo L, Altruda F, Beguinot L, Tarone G, Defilippi P . 1998 EMBO J. 17: 6622–6632
Nagane M, Levitzki A, Gazit A, Cavenee WK, Huang HJ . 1998 Proc. Natl. Acad. Sci. USA 95: 5724–5729
Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, Huang HJ . 1994 Proc. Natl. Acad. Sci. USA 91: 7727–7731
Osherov N, Levitzki A . 1994 Eur. J. Biochem. 225: 1047–1053
Pandey P, Raingeaud J, Kaneki M, Weichselbaum R, Davis RJ, Kufe D, Kharbanda S . 1996 J. Biol. Chem. 271: 23775–23779
Parsons JT, Parsons SJ . 1997 Curr. Opin. Cell. Biol. 9: 187–192
Pearce AK, Humphrey TC . 2001 Trends Cell. Biol. 11: 426–433
Persons DL, Yazlovitskaya EM, Cui W, Pelling JC . 1999 Clin. Cancer Res. 5: 1007–1014
Sato K, Sato A, Aoto M, Fukami Y . 1995 Biochem. Biophys. Res. Commun. 215: 1078–1087
Shiloh Y . 2001 Curr. Opin. Genet. Dev. 11: 71–77
Simizu S, Takada M, Umezawa K, Imoto M . 1998 J. Biol. Chem. 273: 26900–26907
Stoll SW, Benedict M, Mitra R, Hiniker A, Elder JT, Nunez G . 1998 Oncogene 16: 1493–1499
Tice DA, Biscardi JS, Nickles AL, Parsons SJ . 1999 Proc. Natl. Acad. Sci. USA 96: 1415–1420
Wang X, Martindale JL, Holbrook NJ . 2000a J. Biol. Chem. 275: 39435–39443
Wang X, McCullough KD, Franke TF, Holbrook NJ . 2000b J. Biol. Chem. 275: 14624–14631
Wu W, Graves LM, Gill GN, Parsons SJ, Samet JM . 2002 J. Biol. Chem. 277: 24252–24257
Xu W, Doshi A, Lei M, Eck MJ, Harrison SC . 1999 Mol. Cell. 3: 629–638
Yoshizumi M, Abe J, Haendeler J, Huang Q, Berk BC . 2000 J. Biol. Chem. 275: 11706–11712
Young MA, Gonfloni S, Superti-Furga G, Roux B, Kuriyan J . 2001 Cell 105: 115–126
Zhou BB, Elledge SJ . 2000 Nature 408: 433–439
Acknowledgements
This study was supported by the Ministry of Science of the state of Israel and by the Israel Cancer Association through the estate of the late Alexander Smidoda.
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Benhar, M., Engelberg, D. & Levitzki, A. Cisplatin-induced activation of the EGF receptor. Oncogene 21, 8723–8731 (2002). https://doi.org/10.1038/sj.onc.1205980
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DOI: https://doi.org/10.1038/sj.onc.1205980
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