Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.
The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By screening a diverse synthetic chemical library, we have discovered two new classes of small molecules that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/beta-catenin pathway activity. With these small molecules, we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/beta-catenin pathway response in vivo, and we establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.
Chen
Baozhi
B
Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Dodge
Michael E
ME
Tang
Wei
W
Lu
Jianming
J
Ma
Zhiqiang
Z
Fan
Chih-Wei
CW
Wei
Shuguang
S
Hao
Wayne
W
Kilgore
Jessica
J
Williams
Noelle S
NS
Roth
Michael G
MG
Amatruda
James F
JF
Chen
Chuo
C
Lum
Lawrence
L
D060466:Axin Protein; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism*; D012038:Regeneration; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology
D060466:Axin Protein; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin