Anticancer Res. 2025 Nov;45(11):4827-4840. doi: 10.21873/anticanres.17831.
ABSTRACT
BACKGROUND/AIM: We previously reported the therapeutic potential of pimozide against adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1). Pimozide inhibits ubiquitin-specific protease 1 (USP1). In this study, we investigated the functional significance of USP1 and its potential as a therapeutic target for ATL treatment.
MATERIALS AND METHODS: Cellular processes, including proliferation, metabolism, apoptosis, and the expression of USP1 and related regulatory proteins, were assessed.
RESULTS: HTLV-1-infected T cells showed aberrant USP1 protein expression, and USP1 knockdown significantly inhibited their proliferation. Similarly, treatment with pimozide and the USP1 inhibitor SJB3-019A reduced USP1 expression, inhibiting cell proliferation and survival. SJB3-019A decreased the expression of c-Myc, a USP1 target, resulting in G1 cell cycle arrest. Furthermore, it induced caspase-mediated apoptosis by suppressing anti-apoptotic proteins, as well as mitochondrial dysfunction, ROS production, endoplasmic reticulum stress, and DNA damage. SJB3-019A led to a reduction in the critical glycolytic enzyme LDHA, decreasing lactate levels. Additionally, SJB3-019A inhibited the expression of polo-like kinase 1, another USP1 target and a kinase upstream of LDHA and c-Myc. SJB3-019A also suppressed β-catenin expression and IĸBα, RelA, and Akt phosphorylation, indicating NF-ĸB/Akt inhibition.
CONCLUSION: Our study supports the clinical potential of USP1 inhibitors as a novel therapy for ATL.
PMID:41151911 | DOI:10.21873/anticanres.17831
