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

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.

Papillary thyroid cancer in black thyroid: a case report and literature review

“…Previous reports on higher incidence of PTC in black thyroid can be a comprehensible finding, since the recognition of black thyroid predominantly occurs during surgery. Spared pigmentation in malignant tumors compared to surrounding tissue and the unproven carcinogenic activity of minocycline still raise questions on their relationships (9,21). Thus, proper treatment strategy has not yet been established.…”

Effects of Atorvastatin combined with Gefitinib on proliferation, metastatic and autophagy of Colorectal cancer cells

“…; Advanced treatments that are still in the research and development stage, such as gene therapy, cell therapy, targeted immunotherapy, etc. However, each therapy has its drawbacks, such as tumor recurrence, lack of speci city of targets, and resistance to anticancer drugs [20][21][22] . Therefore, it is very necessary to improve and explore the treatment of Colorectal cancer.…”

Pharmacological Efficacy of Repurposing Drugs in the Treatment of Prostate Cancer

“…Minocycline is a tetracycline derivative that inhibits pro-inflammatory cytokines and metalloproteinases that are associated with tumor invasion and metastasis development, and, for this reason, this drug is in clinical trials to be repurposed for PC treatment, in which it has been found that minocycline inhibits LYN kinase and STAT3, suppresses EMT and consequently blocks metastases [ 2 , 34 ]. On the other hand, the chemical modification of tetracyclines (CMT-3) by activating caspase-3 and caspase-9 and by inhibiting metalloproteinases induces apoptosis in PC cells [ 2 , 5 ].…”