Molecular determinants of UCN-01-induced growth inhibition in human lung cancer cells

✍ Scribed by Jitsuo Usuda; Nagahiro Saijo; Kazuya Fukuoka; Hisao Fukumoto; Hyo-Jeong Kuh; Takashi Nakamura; Yasuhiro Koh; Toshihiro Suzuki; Fumiaki Koizumi; Tomohide Tamura; Harubumi Kato; Kazuto Nishio

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: French
• Weight: 153 KB
• Volume: 85
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(20000115)85:2<275::aid-ijc20>3.0.co;2-5

✦ Synopsis

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-01induced 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.