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Contribution of the cyclin‐dependent kinase inhibitor p27 KIP1 to the confluence‐dependent resistance of HT29 human colon carcinoma cells
Author(s) -
DimancheBoitrel MarieThérèse,
Micheau Olivier,
Hammann Arlette,
Haugg Monika,
Eymin Béatrice,
Chauffert Bruno,
Solary Eric
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(19980831)77:5<796::aid-ijc20>3.0.co;2-z
Subject(s) - cell cycle , cisplatin , biology , cancer research , mitosis , cytotoxic t cell , cell growth , transfection , apoptosis , cell culture , microbiology and biotechnology , in vitro , chemotherapy , biochemistry , genetics
We have previously shown that growth of HT29 human colorectal cancer cells at confluence increased their resistance to the cytotoxic agent cisplatin. This study further explores the mechanisms of this resistance phenotype. DNA platination induced by cisplatin exposure is slightly reduced by confluence. However, at an equivalent DNA platination level, non‐confluent cells accumulate in the G 2 /M phase of the cell cycle, demonstrate aberrant mitotic figures and die by apoptosis, while confluent cells progress slowly through the cell cycle, do not reach mitosis and are more resistant to drug‐induced cell death. At a molecular level, cisplatin enhances cyclin B and p34 cdc2 levels and histone H1 kinase activity in non‐confluent, but not in confluent, cells. Furthermore, when HT29 cells reach confluence, expression of the cyclin‐dependent kinase inhibitor p27 Kip1 increases and cells accumulate in the G 0 /G 1 phase of the cell cycle. Transfection‐mediated over‐expression of p27 Kip1 in non‐confluent HT29 cells decreases the cytotoxic activity of cisplatin as well as its ability to trigger apoptosis. Non‐confluent HT29 cells over‐expressing p27 Kip1 are also more resistant to doxorubicin, etoposide and 5‐fluorouracil. Our results suggest that p27 Kip1 contributes to the confluence‐dependent resistance phenotype. Int. J. Cancer 77:796–802, 1998. © 1998 Wiley‐Liss, Inc.