Cyclin A-associated kinase activity is needed for paclitaxel sensitivity.
Cyclin A-associated kinases, such as cyclin-dependent kinase 2 (CDK2), participate in regulating cellular progression from G(1) to S to G(2), and CDK2 has also been implicated in the transition to mitosis. The antitumor properties of CDK inhibitors, alone or in combination with taxanes, are currently being examined in clinical trials. Here, we examined whether the activity of kinases associated with cyclin A (such as CDK2) is important in determining cellular sensitivity to paclitaxel, a taxane and mitotic inhibitor used in chemotherapy for breast and ovarian cancer. We used adenoviral suppression or overexpression to manipulate the expression of CDK2 and cyclin A in one breast cancer and three ovarian cancer cell lines with different sensitivities to paclitaxel and assessed protein expression, kinase activity, cell cycle distribution, and sensitivity to paclitaxel. Transfection of a dominant-negative (DN)-CDK2 evoked resistance to paclitaxel by preventing cellular progression to mitosis through loss of CDK1 activity. Reexpression of wild-type CDK2 in DN-CDK2-transfected cancer cells restored CDK2 activity but not paclitaxel sensitivity. However, expression of cyclin A in DN-CDK2-transfected cells restored their sensitivity to paclitaxel. Although CDK2 activity was not directly involved in paclitaxel sensitivity, cyclin A-associated kinases did up-regulate CDK1 via phosphorylation. We conclude that cyclin A-associated kinase activity is required for these cells to enter mitosis and undergo paclitaxel-induced cell death. Combining taxane chemotherapy with any drug targeting cyclin A-associated kinases (e.g., pure CDK2 inhibitors) should be done with caution, if at all, because of the potential for enhancing taxane resistance.
Takahashi
Takeshi
T
Department of Blood and Marrow Transplantation, Unit 448, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
Yamasaki
Fumiyuki
F
Sudo
Tamotsu
T
Itamochi
Hiroaki
H
Adachi
Susumu
S
Tamamori-Adachi
Mimi
M
Ueno
Naoto T
NT
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000187:drug effects / Q000378:metabolism; D019925:Cyclin A / Q000187:drug effects / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D013912:Threonine / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D019925:Cyclin A; D013912:Threonine; D016203:CDC2 Protein Kinase; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel