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Disruption of IGF‑1R signaling by a novel quinazoline derivative, HMJ‑30, inhibits invasiveness and reverses epithelial-mesenchymal transition in osteosarcoma U‑2 OS cells

  • Authors:
    • Yu-Jen Chiu
    • Mann-Jen Hour
    • Yi-An Jin
    • Chi-Cheng Lu
    • Fuu-Jen Tsai
    • Tai-Lin Chen
    • Hsu Ma
    • Yu-Ning Juan
    • Jai-Sing Yang
  • View Affiliations / Copyright

    Affiliations: Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veteran General Hospital, Taipei 112, Taiwan, R.O.C., School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C., Department of Dermatology, Taipei Medical University Hospital, Taipei 110, Taiwan, R.O.C., Department of Pharmacy, Buddhist Tzu Chi General Hospital, Hualien 970, Taiwan, R.O.C., Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan, R.O.C., Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei 112, Taiwan, R.O.C., Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan, R.O.C.
    Copyright: © Chiu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1465-1478
    |
    Published online on: March 16, 2018
       https://doi.org/10.3892/ijo.2018.4325
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Abstract

Osteosarcoma is the most common primary malignancy of the bone and is characterized by local invasion and distant metastasis. Over the past 20 years, long-term outcomes have reached a plateau even with aggressive therapy. Overexpression of insulin-like growth factor 1 receptor (IGF‑1R) is associated with tumor proliferation, invasion and migration in osteosarcoma. In the present study, our group developed a novel quinazoline derivative, 6-fluoro‑2-(3-fluorophenyl)-4-(cyanoanilino)quinazoline (HMJ‑30), in order to disrupt IGF‑1R signaling and tumor invasiveness in osteosarcoma U‑2 OS cells. Molecular modeling, immune-precipitation, western blotting and phosphorylated protein kinase sandwich ELISA assays were used to confirm this hypothesis. The results demonstrated that HMJ‑30 selectively targeted the ATP-binding site of IGF‑1R and inhibited its downstream phosphoinositide 3-kinase/protein kinase B, Ras/mitogen-activated protein kinase, and IκK/nuclear factor-κB signaling pathways in U‑2 OS cells. HMJ‑30 inhibited U‑2 OS cell invasion and migration and downregulated protein levels and activities of matrix metalloproteinase (MMP)‑2 and MMP-9. An increase in protein levels of tissue inhibitor of metalloproteinase (TIMP)‑1 and TIMP‑2 was also observed. Furthermore, HMJ‑30 caused U‑2 OS cells to aggregate and form tight clusters, and these cells were flattened, less elongated and displayed cobblestone-like shapes. There was an increase in epithelial markers and a decrease in mesenchymal markers, indicating that the cells underwent the reverse epithelial-mesenchymal transition (EMT) process. Overall, these results demonstrated the potential molecular mechanisms underlying the effects of HMJ‑30 on invasiveness and EMT in U‑2 OS cells, suggesting that this compound deserves further investigation as a potential anti-osteosarcoma drug.
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Copy and paste a formatted citation
Spandidos Publications style
Chiu Y, Hour M, Jin Y, Lu C, Tsai F, Chen T, Ma H, Juan Y and Yang J: Disruption of IGF‑1R signaling by a novel quinazoline derivative, HMJ‑30, inhibits invasiveness and reverses epithelial-mesenchymal transition in osteosarcoma U‑2 OS cells. Int J Oncol 52: 1465-1478, 2018.
APA
Chiu, Y., Hour, M., Jin, Y., Lu, C., Tsai, F., Chen, T. ... Yang, J. (2018). Disruption of IGF‑1R signaling by a novel quinazoline derivative, HMJ‑30, inhibits invasiveness and reverses epithelial-mesenchymal transition in osteosarcoma U‑2 OS cells. International Journal of Oncology, 52, 1465-1478. https://doi.org/10.3892/ijo.2018.4325
MLA
Chiu, Y., Hour, M., Jin, Y., Lu, C., Tsai, F., Chen, T., Ma, H., Juan, Y., Yang, J."Disruption of IGF‑1R signaling by a novel quinazoline derivative, HMJ‑30, inhibits invasiveness and reverses epithelial-mesenchymal transition in osteosarcoma U‑2 OS cells". International Journal of Oncology 52.5 (2018): 1465-1478.
Chicago
Chiu, Y., Hour, M., Jin, Y., Lu, C., Tsai, F., Chen, T., Ma, H., Juan, Y., Yang, J."Disruption of IGF‑1R signaling by a novel quinazoline derivative, HMJ‑30, inhibits invasiveness and reverses epithelial-mesenchymal transition in osteosarcoma U‑2 OS cells". International Journal of Oncology 52, no. 5 (2018): 1465-1478. https://doi.org/10.3892/ijo.2018.4325
Copy and paste a formatted citation
x
Spandidos Publications style
Chiu Y, Hour M, Jin Y, Lu C, Tsai F, Chen T, Ma H, Juan Y and Yang J: Disruption of IGF‑1R signaling by a novel quinazoline derivative, HMJ‑30, inhibits invasiveness and reverses epithelial-mesenchymal transition in osteosarcoma U‑2 OS cells. Int J Oncol 52: 1465-1478, 2018.
APA
Chiu, Y., Hour, M., Jin, Y., Lu, C., Tsai, F., Chen, T. ... Yang, J. (2018). Disruption of IGF‑1R signaling by a novel quinazoline derivative, HMJ‑30, inhibits invasiveness and reverses epithelial-mesenchymal transition in osteosarcoma U‑2 OS cells. International Journal of Oncology, 52, 1465-1478. https://doi.org/10.3892/ijo.2018.4325
MLA
Chiu, Y., Hour, M., Jin, Y., Lu, C., Tsai, F., Chen, T., Ma, H., Juan, Y., Yang, J."Disruption of IGF‑1R signaling by a novel quinazoline derivative, HMJ‑30, inhibits invasiveness and reverses epithelial-mesenchymal transition in osteosarcoma U‑2 OS cells". International Journal of Oncology 52.5 (2018): 1465-1478.
Chicago
Chiu, Y., Hour, M., Jin, Y., Lu, C., Tsai, F., Chen, T., Ma, H., Juan, Y., Yang, J."Disruption of IGF‑1R signaling by a novel quinazoline derivative, HMJ‑30, inhibits invasiveness and reverses epithelial-mesenchymal transition in osteosarcoma U‑2 OS cells". International Journal of Oncology 52, no. 5 (2018): 1465-1478. https://doi.org/10.3892/ijo.2018.4325
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