Tyrosine kinase inhibitor STI-571/Gleevec down-regulates the beta-catenin signaling activity.
Beta-Catenin is a critical transducer of the Wnt signal pathway and plays an important role in many developmental and cellular processes. Deregulation of beta-catenin signaling has been observed in a broad range of human tumors. In this report, we investigated whether tyrosine kinase inhibitor STI-571 could inhibit the beta-catenin signaling activity and hence suppress cell proliferation. Our results demonstrated that STI-571 effectively inhibited the constitutive activity of beta-catenin signaling in human colon cancer cells as well as the Wnt1-induced activation of beta-catenin signaling in HOS, HTB-94, and HEK 293 cells. Furthermore, STI-571 was shown to effectively suppress the proliferation of human colon cancer cells. Finally, we demonstrated that the Wnt1-mediated activation of a GAL4-beta-catenin heterologous transcription system was effectively inhibited by STI-571. Thus, our findings suggest that tyrosine phosphorylation may play an important role in regulating beta-catenin signaling activity, and inhibition of this signaling pathway by STI-571 may be further explored as an important target for alternative/adjuvant treatments for a broader range of human cancer.
Zhou
Lan
L
Department of Surgery, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC3079, Chicago, IL 60637, USA.
An
Naili
N
Haydon
Rex C
RC
Zhou
Qixin
Q
Cheng
Hongwei
H
Peng
Ying
Y
Jiang
Wei
W
Luu
Hue H
HH
Vanichakarn
Pantila
P
Szatkowski
Jan Paul
JP
Park
Jae Yoon
JY
Breyer
Benjamin
B
He
Tong-Chuan
TC
D000256:Adenoviridae / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002455:Cell Division; D002460:Cell Line; D003110:Colonic Neoplasms / Q000188:drug therapy; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000096:biosynthesis* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D051176:beta Catenin
D000970:Antineoplastic Agents; D001549:Benzamides; C495270:CTNNB1 protein, human; D017077:Culture Media, Conditioned; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D015534:Trans-Activators; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D051176:beta Catenin; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases