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Targeting neddylation inhibits intravascular survival and extravasation of cancer cells to prevent lung-cancer metastasis

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Abstract

Metastasis is the leading cause of tumor-related death from lung cancer. However, limited success has been achieved in the treatment of lung cancer metastasis due to the lack of understanding of the mechanisms that underlie the metastatic process. In this study, Lewis lung carcinoma (LLC) cells which expressed green fluorescent protein in the nucleus and red fluorescent protein in the cytoplasm were used to record metastatic process in real-time via a whole-mouse imaging system. Using this system, we show the neddylation inhibitor MLN4924 inhibits multiple steps of the metastatic process, including intravascular survival, extravasation, and formation of metastatic colonies, thus finally suppressing tumor metastasis. Mechanistically, MLN4924 efficiently inhibits the expression of MMP2, MMP9, and vimentin and disrupts the actin cytoskeleton at an early stage to impair invasive potential and subsequently causes a DNA damage response, cell cycle arrest, and apoptosis upon long exposure to MLN4924. Furthermore, MMP2 and MMP9 are overexpressed in patient lung adenocarcinoma, which conferred a worse overall survival. Together, targeting the neddylation pathway via MLN4924 suppresses multiple steps of the metastatic process, highlighting the potential therapeutic value of MLN4924 for the treatment of metastatic lung cancer.

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Funding

The Chinese Minister of Science and Technology grant (2016YFA0501800), National Thirteenth Five-Year Science and Technology Major Special Project for New Drug and Development (2017ZX09304001), National Natural Science Foundation of China (Grant Nos. 81820108022, 81625018, 81572340, 81871870, 81702244, 81772470, and 81602072), Program of Shanghai Academic/Technology Research Leader (18XD1403800), and Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056) supported this work.

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Contributions

LJJ and YYJ conceived the general framework of this study. YYJ and LJJ designed experiments. YYJ, YPL, LHL, WC, and HQ performed experiments. PYZ, RMH, XGY, XY, LSJ, and JHY provided technical, administrative, or material support. YYJ, YPL, and LSZ prepared the manuscript. LJJ supervised this study.

Corresponding authors

Correspondence to Peiyong Zheng or Lijun Jia.

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All animal studies were performed in accordance with animal protocol procedures approved by the Institutional Animal Care and Use Committee of Shanghai University of Traditional Chinese Medicine.

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Jiang, Y., Liang, Y., Li, L. et al. Targeting neddylation inhibits intravascular survival and extravasation of cancer cells to prevent lung-cancer metastasis. Cell Biol Toxicol 35, 233–245 (2019). https://doi.org/10.1007/s10565-019-09472-w

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  • DOI: https://doi.org/10.1007/s10565-019-09472-w

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