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Mechanism of antitumor action of PKC activator, gnidimacrin
Author(s) -
Yoshida Mitsuzi,
Yokokura Hisayuki,
Hidaka Hiroyoshi,
Ikekawa Tetsuro,
Saijo Nagahiro
Publication year - 1998
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(19980717)77:2<243::aid-ijc13>3.0.co;2-c
Subject(s) - protein kinase c , mechanism of action , k562 cells , activator (genetics) , cell culture , phorbol , biology , kinase , pharmacology , microbiology and biotechnology , chemistry , receptor , biochemistry , in vitro , genetics
Daphnane‐type diterpene gnidimacrin isolated from the Chinese plant Stellera chamaejasme L. is an antitumor agent that activates protein kinase C (PKC). The mechanism of antitumor action of gnidimacrin and the possible involvement of PKC were examined using sensitive K562 and refractory HLE cells. Gnidimacrin did bind to K562 cells 3 times more than to HLE cells. Immunoblot analyses revealed pronounced PKCβII expression in gnidimacrin sensitive cell lines including K562 cells, while refractory HLE cells strongly expressed PKCα, but not PKCβII. In a 24‐hr exposure of K562 cells to gnidimacrin, G 1 phase arrest and inhibition of cdk2 kinase activity was found at growth‐inhibitory concentration (0.0005 μg/ml). Complete inhibition of cdk2 activity and maximum G 1 phase arrest were observed at 0.005 μg/ml, however, these biological effects were reduced at 0.05 μg/ml (260 times the 50% inhibitory concentration). Cellular PKC after a 24‐hr exposure was examined by immunoblot analysis and specific binding of [ 3 H]phorbol‐12,13‐dibutyrate as a ligand of PKC. Expression and the amount of functional PKC of K562 cells were not changed at 0.002 μg/ml, but down‐regulated to less than 1/10th of the control at 0.05 μg/ml. The reduction of biological effects at 0.05 μg/ml is most likely due to PKC down‐regulation. Our results suggest that PKC (particularly βII) is one of the major determinants of the ability of cells to respond to gnidimacrin and that the antitumor action might be associated with cell‐cycle regulation through suppression of cdk2 activity. Int. J. Cancer 77:243–250, 1998.© 1998 Wiley‐Liss, Inc.