A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy

Tsung I. Hsu, Ying Jung Chen, Chia Yang Hung, Yi Chang Wang, Sin Jin Lin, Wu Chou Su, Ming Derg Lai, Sang Yong Kim, Qiang Wang, Keduo Qian, Masuo Goto, Yu Zhao, Yoshiki Kashiwada, Kuo Hsiung Lee, Wen Chang Chang, Jan Jong Hung

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13 Citations (Scopus)

Abstract

Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer.

Original languageEnglish
Pages (from-to)13671-13687
Number of pages17
JournalOncotarget
Volume6
Issue number15
Publication statusPublished - 2015

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Keywords

  • ER stress
  • Metastasis
  • syk023
  • Synaptopodin

ASJC Scopus subject areas

  • Oncology

Cite this

Hsu, T. I., Chen, Y. J., Hung, C. Y., Wang, Y. C., Lin, S. J., Su, W. C., Lai, M. D., Kim, S. Y., Wang, Q., Qian, K., Goto, M., Zhao, Y., Kashiwada, Y., Lee, K. H., Chang, W. C., & Hung, J. J. (2015). A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy. Oncotarget, 6(15), 13671-13687.