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Effects of the tyrosine‐kinase inhibitor geldanamycin on ligand‐induced HER‐2/NEU activation, receptor expression and proliferation of HER‐2‐positive malignant cell lines
Author(s) -
Hartmann Frank,
Horak Eva M.,
Cho Cheryl,
Lupu Ruth,
Bolen Joseph B.,
StetlerStevenson Mary A.,
Pfreundschuh Michael,
Waldmann Thomas A.,
Horak Ivan D.
Publication year - 1997
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19970117)70:2<221::aid-ijc14>3.0.co;2-l
Subject(s) - geldanamycin , tyrosine kinase , cancer research , tyrosine kinase inhibitor , receptor tyrosine kinase , receptor protein tyrosine kinases , ligand (biochemistry) , chemistry , cell culture , receptor , cell growth , tyrosine , microbiology and biotechnology , biology , hsp90 , biochemistry , genetics , gene , cancer , heat shock protein
Geldanamycin belongs to the family of benzoquinoid ansamycin tyrosine‐kinase inhibitors. We have examined its effects on Her‐2/neu kinase activity, protein expression level, and proliferation of Her‐2 + malignant cells. In SK‐BR‐3 breast‐cancer cells, short‐time treatment with geldanamycin completely abrogated gp30‐ligand‐induced activation of Her‐2 without a change of receptor‐expression level. Longer treatment of intact cells with geldanamycin induced decreased steady‐state Her‐2 autophosphorylation activity, which correlated with reduction of Her‐2 protein expression and phosphotyrosine content of several proteins. The decrease was time‐ and dose‐dependent, starting after 1 hr at 100 nM concentration and reaching completion by 24 hr. The reduction of the Her‐2 protein level probably resulted from increased degradation, since the Her‐2 mRNA level remained constant. Geldanamycin effects were not specific for Her‐2, since the non‐receptor tyrosine‐kinase fyn was inhibited equally. In contrast to these results, protein‐kinase‐C activity was not affected. In 3 other malignant cell lines expressing different amounts of Her‐2 (SK‐BR‐3 > SK‐OV‐3 > OVCAR3 > MCF7), geldanamycin also effectively reduced Her‐2‐kinase activity proportionally to the decrease of protein expression. In contrast, in a [ 3 H]‐thymidine‐uptake assay, cell growth was meaningfully inhibited by geldanamycin at nanomolar concentrations only in SK‐BR‐3 (IC 50 2nM) and MCF7 (IC 50 20nM), while OVCAR3 was only moderately sensitive (IC 50 2μM) and SK‐OV‐3 was clearly resistant to geldanamycin. In direct comparison with herbimycin A, another benzoquinoid ansamycin that has been more thoroughly characterized, the biologic effects of geldanamycin were more pronounced. Int. J. Cancer, 70:221–229, 1997. © 1997 Wiley‐Liss, Inc.