Int J Biol Sci 2022; 18(6):2540-2552. doi:10.7150/ijbs.70708 This issue

Research Paper

Minocycline binds and inhibits LYN activity to prevent STAT3-meditated metastasis of colorectal cancer

Ling Yang1*, Jing Yang2*, Hua Liu2*, Jingbin Lan2*, Ying Xu4, Xiaobo Wu1, Yushan Mao1, Dongming Wu4, Kejian Pan2✉, Tao Zhang2,3✉

1. School of Basic Medical science, Chengdu Medical College, Chengdu, China.
2. School of Bioscience and Technology, Chengdu Medical College, Chengdu, China.
3. The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China.
4. School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China.
*These authors contributed equally to this work.

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Citation:
Yang L, Yang J, Liu H, Lan J, Xu Y, Wu X, Mao Y, Wu D, Pan K, Zhang T. Minocycline binds and inhibits LYN activity to prevent STAT3-meditated metastasis of colorectal cancer. Int J Biol Sci 2022; 18(6):2540-2552. doi:10.7150/ijbs.70708. Available from https://www.ijbs.com/v18p2540.htm

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Abstract

Graphic abstract

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Metastasis is a major cause of CRC recurrence and mortality. Several antibiotic drugs have been reported to exert potential anticancer activities, however, whether and how the tetracycline antibiotic minocycline exhibit tumor suppressive effect on CRC remains unknown. Here, we found that minocycline markedly inhibits the epithelial-mesenchymal transition (EMT) process and metastasis of CRC cells both in vitro and in vivo. Using chemical proteomics screening combined with docking analysis and site-directed mutagenesis, we identified LYN as a direct bind target of minocycline, and Ala255 of LYN is required for minocycline binding. Mechanistically, minocycline binding inactivates LYN, leading to STAT3 inactivation and EMT suppression, thereby inhibits CRC metastasis. Tissue microarray analysis further confirmed the clinical relevance of LYN-STAT3 axis in the EMT and progression of CRC. In addition to CRC, minocycline also significantly prevents EMT process and inhibits the metastasis of several other cancer types. Our findings elucidate the mechanism of action of minocycline for the inhibition of CRC metastasis by LYN binding, and suggest that repurposing minocycline may represent a promising strategy for the treatment of advanced CRC and other cancer types.

Keywords: Minocycline, LYN, STAT3, EMT, colorectal cancer