FH535 suppresses osteosarcoma growth in vitro and inhibits wnt signaling through tankyrases

Carl T. Gustafson, Tewodros Mamo, Kristen L. Shogren, Avudaiappan Maran, Michael J Yaszemski

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number285
JournalFrontiers in Pharmacology
Volume8
Issue numberMAY
DOIs
StatePublished - May 23 2017

Fingerprint

Tankyrases
Osteosarcoma
Growth
Catenins
Enzymes
Adjuvant Chemotherapy
Osteoblasts
Doxorubicin
FH535
In Vitro Techniques
Neoplasms
Neoplasm Metastasis
Bone and Bones
Cell Line

Keywords

  • Osteosarcoma
  • PARP1
  • Small molecule chemotherapy
  • Tankyrase inhibitor
  • Wnt signaling

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

FH535 suppresses osteosarcoma growth in vitro and inhibits wnt signaling through tankyrases. / Gustafson, Carl T.; Mamo, Tewodros; Shogren, Kristen L.; Maran, Avudaiappan; Yaszemski, Michael J.

In: Frontiers in Pharmacology, Vol. 8, No. MAY, 285, 23.05.2017.

Research output: Contribution to journalArticle

Gustafson, Carl T. ; Mamo, Tewodros ; Shogren, Kristen L. ; Maran, Avudaiappan ; Yaszemski, Michael J. / FH535 suppresses osteosarcoma growth in vitro and inhibits wnt signaling through tankyrases. In: Frontiers in Pharmacology. 2017 ; Vol. 8, No. MAY.
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