Gustafson Carl T, Mamo Tewodros, Shogren Kristen L, Maran Avudaiappan, Yaszemski Michael J
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Clinic, RochesterMN, United States.
Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Mayo Clinic, RochesterMN, United States.
Front Pharmacol. 2017 May 23;8:285. doi: 10.3389/fphar.2017.00285. eCollection 2017.
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 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.
骨肉瘤（OS）是一种侵袭性原发性骨肿瘤，其Wnt信号通路异常激活。经典Wnt信号级联已被证明可通过激活β-连环蛋白来驱动癌症进展和转移。因此，Wnt靶点的小分子抑制剂正被探索用作一线或辅助化疗药物。在本研究中，我们研究了Wnt信号拮抗剂FH535抑制OS细胞生长的能力。我们发现FH535对所有测试的OS细胞系（143b、U2OS、SaOS-2、HOS、K7M2）均具有细胞毒性，但正常人类成骨细胞对其耐受性良好。此外，我们建立了多柔比星耐药OS模型，发现这些细胞对FH535治疗高度敏感。我们的分析提供了证据，表明FH535强烈抑制经典Wnt信号的标志物。此外，我们的研究结果表明Axin2的PAR修饰减少，表明端锚聚合酶1/2酶受到抑制。此外，我们观察到在FH535存在的情况下PARP1的自身修饰受到抑制，表明PARP1酶活性受到抑制。这些数据提供了证据，表明FH535通过端锚聚合酶1/2酶发挥作用来抑制Wnt信号，并且可以作为一种有效的化疗药物来控制骨肉瘤进行探索。
