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Molecular determinants of UCN‐01‐induced growth inhibition in human lung cancer cells
Author(s) -
Usuda Jitsuo,
Saijo Nagahiro,
Fukuoka Kazuya,
Fukumoto Hisao,
Kuh HyoJeong,
Nakamura Takashi,
Koh Yasuhiro,
Suzuki Toshihiro,
Koizumi Fumiaki,
Tamura Tomohide,
Kato Harubumi,
Nishio Kazuto
Publication year - 2000
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(20000115)85:2<275::aid-ijc20>3.0.co;2-5
Subject(s) - cyclin dependent kinase 6 , cell growth , cell culture , cell cycle , cancer research , biology , growth inhibition , cell , in vivo , cyclin dependent kinase 2 , medicine , chemistry , microbiology and biotechnology , biochemistry , genetics
UCN‐01 (7‐hydroxystaurosporine) inhibits the growth of various malignant cell lines in vitro and in vivo . In this study, a human small cell lung carcinoma subline resistant to UCN‐01, SBC‐3/UCN, was established and characterized. SBC‐3/UCN cells showed 8‐fold greater resistance to the UCN‐01‐induced growth‐inhibitory effect than the parent cells, SBC‐3. No UCN‐01‐induced G1 accumulation in SBC‐3 cells was observed in SBC‐3/UCN cells and decreased expression of phosphorylated RB protein was found in SBC‐3 cells. Neither basal expression nor induction of p21 Cip1 by UCN‐01 treatment was detected in the SBC‐3/UCN cell line. An inhibitory effect of UCN‐01 on CDK2 activity, which is mediated by p21 Cip1 /CDK2 complex formation upon UCN‐01 treatment, was observed in SBC‐3 but not in SBC‐3/UCN cells. SBC‐3/UCN showed higher CDK6 activity than SBC‐3 cells. UCN‐01 did not inhibit the CDK4 and CDK6 activities in both cells. We screened the cell cycle regulatory molecules associated with G 1 /S progression and found a remarked decrease in interferon regulatory factor 1 (IRF‐1), which is known to cooperate with p53 in p21 Cip1 induction. Our results suggest that p21 Cip1 regulation via the IRF‐1‐associated pathway may represent a major determinant of UCN‐01‐induced growth inhibition in human lung cancer cells. Int. J. Cancer 85:275–280, 2000. ©2000 Wiley‐Liss, Inc.