TY - JOUR
T1 - FH535 suppresses osteosarcoma growth in vitro and inhibits wnt signaling through tankyrases
AU - Gustafson, Carl T.
AU - Mamo, Tewodros
AU - Shogren, Kristen L.
AU - Maran, Avudaiappan
AU - Yaszemski, Michael J.
N1 - Funding Information:
We acknowledge funding support from the Predoctoral Training Program in Molecular Pharmacology (NIH T32 GM072474-10, CG; Director: Larry Karnitz), the Mayo Clinic Orthopaedic Research Review Committee (CG), the NIH/NCI Predoctoral National Research Service Award (1F31CA206388-01A1, TM), the Predoctoral Training Program in Musculoskeletal Research (NIH 5T32 AR56950-7, TM; Director: Jennifer Westendorf), and the John and Posy Krehbiel Endowed Professorship of Orthopedic Surgery and Biomedical Engineering (MY). We acknowledge Nicole Murray, Martin Fernandez-Zapico, and Joel Reid for their thoughtful advice and discussions. In addition, we thank Scott Kaufmann, Xue W. Meng, Roman Thaler, and Christopher Paradise for methodological expertise and guidance. The members of the Mayo Clinic Microscopy and Cell Analysis Core lab, as well as the members of the Mayo Clinic Gene Expression Core lab are thanked for assistance in experimental procedures.
Publisher Copyright:
© 2017 Gustafson, Mamo, Shogren, Maran and Yaszemski.
PY - 2017/5/23
Y1 - 2017/5/23
N2 - Osteosarcoma (OS) is an aggressive primary bone tumor which exhibits aberrantly activated Wnt signaling. The canonical Wnt signaling cascade has been shown to drive cancer progression and metastasis through the activation of β-catenin. Hence, small molecule inhibitors of Wnt targets are being explored as primary or adjuvant chemotherapy. In this study, we have investigated the ability of FH535, an antagonist of Wnt signaling, to inhibit the growth of OS cells. We found that FH535\ was cytotoxic in all OS cell lines which were tested (143b, U2OS, SaOS-2, HOS, K7M2) but well tolerated by normal human osteoblast cells. Additionally, we have developed an in vitro model of doxorubicin-resistant OS and found that these cells were highly responsive to FH535 treatment. Our analysis provided evidence that FH535 strongly inhibited markers of canonical Wnt signaling. In addition, our findings demonstrate a reduction in PAR-modification of Axin2 indicating inhibition of the tankyrase 1/2 enzymes. Moreover, we observed inhibition of auto-modification of PARP1 in the presence of FH535, indicating inhibition of PARP1 enzymatic activity. These data provide evidence that FH535 acts through the tankyrase 1/2 enzymes to suppress Wnt signaling and could be explored as a potent chemotherapeutic agent for the control of OS.
AB - Osteosarcoma (OS) is an aggressive primary bone tumor which exhibits aberrantly activated Wnt signaling. The canonical Wnt signaling cascade has been shown to drive cancer progression and metastasis through the activation of β-catenin. Hence, small molecule inhibitors of Wnt targets are being explored as primary or adjuvant chemotherapy. In this study, we have investigated the ability of FH535, an antagonist of Wnt signaling, to inhibit the growth of OS cells. We found that FH535\ was cytotoxic in all OS cell lines which were tested (143b, U2OS, SaOS-2, HOS, K7M2) but well tolerated by normal human osteoblast cells. Additionally, we have developed an in vitro model of doxorubicin-resistant OS and found that these cells were highly responsive to FH535 treatment. Our analysis provided evidence that FH535 strongly inhibited markers of canonical Wnt signaling. In addition, our findings demonstrate a reduction in PAR-modification of Axin2 indicating inhibition of the tankyrase 1/2 enzymes. Moreover, we observed inhibition of auto-modification of PARP1 in the presence of FH535, indicating inhibition of PARP1 enzymatic activity. These data provide evidence that FH535 acts through the tankyrase 1/2 enzymes to suppress Wnt signaling and could be explored as a potent chemotherapeutic agent for the control of OS.
KW - Osteosarcoma
KW - PARP1
KW - Small molecule chemotherapy
KW - Tankyrase inhibitor
KW - Wnt signaling
UR - http://www.scopus.com/inward/record.url?scp=85019623623&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019623623&partnerID=8YFLogxK
U2 - 10.3389/fphar.2017.00285
DO - 10.3389/fphar.2017.00285
M3 - Article
AN - SCOPUS:85019623623
VL - 8
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
SN - 1663-9812
IS - MAY
M1 - 285
ER -