Triazolo-indazole-trione-mediated disruption of Wnt/β-catenin pathway drives both autophagic and paraptotic cell deaths in colorectal cancer cells

Abstract

Aberrant activation of the Wnt/β-catenin signaling pathway is a hallmark of numerous human cancers, including colorectal carcinoma. Targeting this pathway has been shown to effectively induce cancer cell death and inhibit tumor progression. In this study, we investigated the anti-tumor effects of HR10, a novel synthetic compound, in colorectal carcinoma cells. HR10 significantly suppressed cell viability in HCT-116, HCT-15, HT-29, and SNU-C2A cells while having minimal impact on normal colon cells. Mechanistically, HR10 induced autophagy by upregulating Atg7, p-Beclin-1, and Beclin-1, and triggered paraptosis through the downregulation of Alix, a key inhibitor of this process. Additionally, HR10 increased reactive oxygen species (ROS) levels, disrupted mitochondrial membrane potential, and activated ER stress by elevating ATF4 and CHOP expression. Moreover, HR10 inhibited the Wnt/β-catenin pathway by downregulating β-catenin, Wnt3a, and FZD-1, while enhancing β-TrCP and p-GSK3β (Tyr216). Knockdown of β-catenin further confirmed that HR10-mediated autophagy and paraptosis were directly associated with the suppression of the Wnt/β-catenin signaling cascade. These results highlight the dual mechanisms of autophagy and paraptosis induction, positioning HR10 as a promising therapeutic candidate for colorectal cancer. Overall, our findings demonstrate that HR10 effectively targets the Wnt/β-catenin signaling pathway, inducing autophagic and paraptotic cell death, and providing a potential therapeutic strategy for colorectal carcinoma.