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Rationale: Colorectal cancer (CRC) is one of the most common cancers worldwide. Ciclopirox olamine (CPX) has recently been identified to be a promising anticancer candidate; however, novel activities and detailed mechanisms remain to be uncovered.Methods: The cytotoxic potential of CPX towards CRC cells was examined in vitro and in vivo. The global gene expression pattern, ROS levels, mitochondrial function, autophagy, apoptosis, etc. were determined between control and CPX-treated CRC cells.Results: We found that CPX inhibited CRC growth by inhibiting proliferation and inducing apoptosis both in vitro and in vivo. The anti-cancer effects of CPX involved the downregulation of DJ-1, and overexpression of DJ-1 could reverse the cytotoxic effect of CPX on CRC cells. The loss of DJ-1 resulted in mitochondrial dysfunction and ROS accumulation, thus leading to CRC growth inhibition. The cytoprotective autophagy was provoked simultaneously, and blocking autophagy pharmacologically or genetically could further enhance the anti-cancer efficacy of CPX.Conclusion: Our study demonstrates that DJ-1 loss-induced ROS accumulation plays a pivotal role in CPX-mediated CRC inhibition, providing a further understanding for CRC treatment via modulating compensatory protective autophagy.

Redox imbalance is resulted from the destruction of balance between oxidants and antioxidants. The dominant oxidants are reactive oxygen species (ROS), which are involved in multiple cellular processes by physiologically transporting signal as a second messenger or pathologically oxidizing DNA, lipids, and proteins. Generally speaking, low concentration of ROS is indispensable for cell survival and proliferation. However, high concentration of ROS is cytotoxic. Additionally, ROS are now known to induce the oxidative modification of macromolecules especially proteins. The redox modification of proteins is involved in numerous biological processes related to diseases including CRC. Herein, we attempt to afford an overview that highlights the crosstalk between redox imbalance and CRC.

Metastasis remains a big barrier for the clinical treatment of colorectal cancer (CRC). Our previous proteomics analysis identified DJ-1 as a potential metastasis biomarker of CRC. In this study, we found that DJ-1 was upregulated in CRC. The levels of DJ-1 were closely correlated with the depths of invasion and predicted patient outcome. Enforced expression of DJ-1 could enhance CRC proliferation and metastasis in vitro and in vivo by stimulating Wnt-β-catenin signaling. Specifically, DJ-1-induced β-catenin nuclear translocation stimulated TCF transcription activity, which promoted BMP4 expression for CRC cell migration and invasion, and elevated CCND1 expression for CRC cell proliferation, respectively. Furthermore, DJ-1-induced Wnt signaling activation was dependent on PLAGL2 expression. In conclusion, our study demonstrates that DJ-1 can promote CRC metastasis by activating PLAGL2–Wnt–BMP4 axis, suggesting novel therapeutic opportunities for postoperative adjuvant therapy in CRC patients.