A novel chalcone analog inhibits cancer stemness in CD44+ and CD133+ populations via suppression of ERK signaling

초록

Cancer stem-like cells (CSC) that express cluster of differentiation (CD)44 or CD133 contribute to tumor aggressiveness, therapeutic resistance, and disease recurrence across multiple malignancies. Consequently, current therapeutic modalities frequently fail to achieve durable disease control; hence, novel therapeutic strategies are urgently required. Therapeutic strategies that disrupt CSC maintenance may therefore contribute to more durable cancer control. Suitably, chalcone-based analogs have emerged as promising anticancer candidates. Therefore, this study aimed to investigate the effects of a novel chalcone analog 1 (UR-1) on CSC populations characterized by CD44+ or CD133+ phenotypes using complementary three-dimensional culture systems and in vivo models. CD44+ or CD133+ CSC populations were enriched from human head and neck squamous cell carcinoma, gastric cancer, breast cancer, lung cancer, colorectal cancer, and hepatocellular carcinoma cell lines. The effects of the novel chalcone-based 1 (UR-1) on CSC-associated phenotypes were evaluated in vitro and in organoid-derived xenograft models. Stemness-associated markers and apoptotic signaling were assessed via immunoblotting and immunofluorescence analyses. Structure-based analyses revealed that UR-1 favorably interacts with surface-accessible binding pockets of both CD44 and CD133, with comparable binding affinity toward the two CSC markers. Mechanistically, UR-1 markedly suppressed ERK phosphorylation (p-ERK), thereby attenuating downstream signaling associated with CSC maintenance. Consistent with these findings, UR-1 markedly suppressed the expression of stemness-associated proteins and impaired spheroid- and organoid-forming capacity in CD44+ cancer cells derived from multiple tumor types. Similar inhibitory effects were observed in CD133+ CSC populations derived from lung, colorectal, and liver cancers, where UR-1 reduced three-dimensional growth and stemness marker expression. In CD133+ cancer organoid models, UR-1 disrupted organoid architecture and decreased the expression of CD133 and SOX2. Furthermore, UR-1 treatment markedly attenuated stemness marker expression and induced cleaved caspase-3-positive apoptotic signaling in CD44+ or CD133+ organoid-derived xenografts. These findings demonstrate that UR-1 suppresses stemness and promotes apoptosis in CD44+ and CD133+ CSC populations in association with suppression of ERK phosphorylation. By targeting this critical signaling axis, UR-1 attenuates CSC-driven tumor progression and therapeutic resistance, highlighting its potential as a promising therapeutic candidate.

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