Synergistic autophagy effect of miR-212-3p in zoledronic acid-treated in vitro and orthotopic in vivo models and in patient-derived osteosarcoma cells

Ju Yeon Oh, Eun Ho Kim, Yeon Joo Lee, Sei Sai, Sun Ha Lim, Jang Woo Park, Hye Kyung Chung, Joon Kim, Guillaume Vares, Akihisa Takahashi, Youn Kyoung Jeong, Mi Sook Kim, Chang Bae Kong

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3 Citations (Scopus)

Abstract

Osteosarcoma (OS) originates from osteoid bone tissues and is prone to metastasis, resulting in a high mortality rate. Although several treatments are available for OS, an effective cure does not exist for most patients with advanced OS. Zoledronic acid (ZOL) is a third-generation bisphosphonate that inhibits osteoclast-mediated bone resorption and has shown efficacy in treating bone metastases in patients with various types of solid tumors. Here, we sought to clarify the mechanisms through which ZOL inhibits OS cell proliferation. ZOL treatment inhibited OS cell proliferation, viability, and colony formation. Autophagy inhibition by RNA interference against Beclin-1 or ATG5 inhibited ZOL-induced OS cell death. ZOL induced autophagy by repressing the protein kinase B/mammalian target of rapamycin/p70S6 kinase pathway and extracellular signal-regulated kinase signaling-dependent autophagy in OS cell lines and patient-derived OS cells. Microarrays of miRNA showed that ZOL increased the levels of miR-212-3p, which is known to play an important role in autophagy, in OS in vitro and in vivo systems. Collectively, our data provided mechanistic insight into how increased miR-212-3p through ZOL treatment induces autophagy synergistically in OS cells, providing a preclinical rationale for conducting a broad-scale clinical evaluation of ZOL + miR-212-3p in treating OS.

Original languageEnglish
Article number1812
JournalCancers
Volume11
Issue number11
DOIs
Publication statusPublished - 2019 Nov

Keywords

  • Autophagy
  • MiR-212
  • Osteosarcoma
  • Zoledronic acid

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Oh, J. Y., Kim, E. H., Lee, Y. J., Sai, S., Lim, S. H., Park, J. W., Chung, H. K., Kim, J., Vares, G., Takahashi, A., Jeong, Y. K., Kim, M. S., & Kong, C. B. (2019). Synergistic autophagy effect of miR-212-3p in zoledronic acid-treated in vitro and orthotopic in vivo models and in patient-derived osteosarcoma cells. Cancers, 11(11), [1812]. https://doi.org/10.3390/cancers11111812