Repurposing diacerein to suppress colorectal cancer growth by inhibiting the DCLK1/STAT3 signaling pathway

Double cortin-like kinase 1 (DCLK1) is highly expressed in a variety of cancers, particularly in human colorectal cancer (CRC). Diacerein, a non-steroid analog, has been clinically approved for the treatment of osteoarthritis. We investigated the effect of diacerein on CRC growth and migration and its possible mechanism in vitro and in vivo. MTT assay, colony formation, wound-healing, transwell, flow cytometry and Hoechst 33342 staining analysis were used to measure cell proliferation, migration, and apoptosis. Proteome microarray assay and western blot analysis were used to explore the specific mechanism through which diacerein exerts its effects. Here, we report that diacerein suppresses DCLK1-dependent CRC growth in vitro and in vivo. High-throughput proteomics microarray and molecular docking analyses revealed that diacerein directly binds to DCLK1. Mechanistically, we show that P-STAT3 expression was decreased after DCLK1 inhibition using diacerein or a specific DCLK1 siRNA. Moreover, diacerein inhibited the DCLK1/STAT3 signaling pathway, as well as its downstream targets, including MCL-1, VEGF and survivin. Diacerein also inhibited CRC in a mouse model. Our results provide strong evidence for the use of diacerein in the treatment of CRC, in which DCLK1 plays a vital role in CRC development. It is conceivable that diacerein can be further probed as a distinctive DCLK1 inhibitor in CRC therapy.