Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells.
Maintenance of chromosomal ends (telomeres) directly contributes to cancer cell immortalization. The telomere protection enzymes belonging to the tankyrase (Tnks) subfamily of poly(ADP-ribose) polymerases (PARPs) have recently been shown to also control transcriptional response to secreted Wnt signaling molecules. Whereas Tnks inhibitors are currently being developed as therapeutic agents for targeting Wnt-related cancers and as modulators of Wnt signaling in tissue-engineering agendas, their impact on telomere length maintenance remains unclear. Here, we leveraged a collection of Wnt pathway inhibitors with previously unassigned mechanisms of action to identify novel pharmacophores supporting Tnks inhibition. A multifaceted experimental approach that included structural, biochemical, and cell biological analyses revealed two distinct chemotypes with selectivity for Tnks enzymes. Using these reagents, we revealed that Tnks inhibition rapidly induces DNA damage at telomeres and telomeric shortening upon long-term chemical exposure in cultured cells. On the other hand, inhibitors of the Wnt acyltransferase Porcupine (Porcn) elicited neither effect. Thus, Tnks inhibitors impact telomere length maintenance independently of their affects on Wnt/β-catenin signaling. We discuss the implications of these findings for anticancer and regenerative medicine agendas dependent upon chemical inhibitors of Wnt/β-catenin signaling.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Ozlem
O
Kulak
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Hua
H
Chen
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Brody
B
Holohan
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Xiaofeng
X
Wu
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Huawei
H
He
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Dominika
D
Borek
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Zbyszek
Z
Otwinowski
Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Kiyoshi
K
Yamaguchi
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Lauren A
LA
Garofalo
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Zhiqiang
Z
Ma
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Woodring
W
Wright
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Chuo
C
Chen
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Jerry W
JW
Shay
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA Xuewu.zhang@utsouthwestern.edu Lawrence.lum@utsouthwestern.edu.
Xuewu
X
Zhang
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Xuewu.zhang@utsouthwestern.edu Lawrence.lum@utsouthwestern.edu.
Lawrence
L
Lum
D015153:Blotting, Western; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007094:Imides / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D034622:RNA Interference; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D059506:Telomere Shortening / Q000187:drug effects*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*
D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D007094:Imides; D011804:Quinolines; D054852:Small Molecule Libraries; D038501:Tankyrases; D051176:beta Catenin; C585534:IWR-1 compound; C544261:XAV939; C418109:TNKS protein, human