Imatinib mesylate induces quiescence in gastrointestinal stromal tumor cells through the CDH1-SKP2-p27Kip1 signaling axis.
Gastrointestinal stromal tumors (GIST) are caused by activating mutations in the KIT or platelet-derived growth factor receptor alpha receptor tyrosine kinase genes. Approximately 85% of GIST patients treated with imatinib mesylate achieve disease stabilization, however, often in the presence of residual tumor masses. Complete remissions are rare and a substantial proportion of patients develop resistance to imatinib. Our study was designed to determine whether imatinib-associated responses may account for these clinical findings. We report here that imatinib stimulates cellular quiescence in a proportion of GIST cells as evidenced by up-regulation of the CDK inhibitor p27(Kip1), loss of cyclin A, and reduced BrdUrd incorporation. Mechanistically, these events are associated with an imatinib-induced modulation of the APC/CDH1 signaling axis. Specifically, we provide evidence that imatinib down-regulates SKP2 and that this event is associated with increased nuclear CDH1, an activator of the APC that has been shown to regulate SKP2 stability. We also show that those GIST cells that do not undergo apoptosis in response to imatinib overexpress nuclear p27(Kip1), indicating that they have withdrawn from the cell cycle and are quiescent. Lastly, we provide evidence that a fraction of primary GISTs with high SKP2 expression levels may have an increased risk of disease progression. Taken together, our results support a model in which GIST cells that do not respond to imatinib by apoptosis are removed from the proliferative pool by entering quiescence through modulation of the APC/CDH1-SKP2-p27(Kip1) signaling axis. These results encourage further studies to explore compounds that modulate this pathway as antitumor agents in GISTs.
Liu
Ying
Y
Molecular Virology Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania15213, USA.
Perdreau
Sophie A
SA
Chatterjee
Payel
P
Wang
Linan
L
Kuan
Shih-Fan
SF
Duensing
Anette
A
D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D015820:Cadherins / Q000378:metabolism*; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D046888:Tissue Array Analysis; D015854:Up-Regulation
D015703:Antigens, CD; D000970:Antineoplastic Agents; D001549:Benzamides; C513384:CDH1 protein, human; C436291:CDKN1B protein, human; D015820:Cadherins; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011743:Pyrimidines; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000068877:Imatinib Mesylate