Ivermectin inhibits the growth of esophageal squamous cell carcinoma by activating ATF4-mediated endoplasmic reticulum stress-autophagy pathway

Esophageal squamous cell carcinoma (ESCC) is one of the most common form of malignancies in the world. However, there is currently a lack of effective chemotherapeutic drugs for ESCC, and it is urgent to develop new and safe drugs for this disease. Ivermectin is a broad-spectrum antiparasitic drug with demonstrable antitumor activity. However, the precise cellular and molecular mechanisms of ivermectin in cancers growth inhibition remain unclear. In this study, we report a role of ivermectin in ESCC suppression by activating the endoplasmic reticulum (ER) stress and autophagy. In transcriptome analysis, we found that ATF4 and DDIT3 are involved in ER stress activation by ivermectin. Moreover, ivermectin treatment suppressed the growth of ESCC xenograft tumors in nude mice. Taken together, our results identify the antitumor molecular basis of ivermectin targeting the ER stress-autophagy pathway and suggest that ivermectin is a potential drug for the treatment of ESCC.