SUMOylation inhibitor TAK‑981 suppresses proliferation and induces apoptosis in SK‑UT‑1B uterine leiomyosarcoma cells

Uterine leiomyosarcoma (Ut‑LMS) is an aggressive smooth muscle malignancy with limited therapeutic options and a poor prognosis, underscoring the need for new molecularly‑targeted therapies. TAK‑981 (subasumstat), a selective inhibitor of small ubiquitin‑like modifier (SUMO)‑activating enzymes, exhibits antitumor activity in several types of cancer; however, to the best of our knowledge, its therapeutic potential in Ut‑LMS has not been explored. The current study evaluated the effects of TAK‑981 on human Ut‑LMS cells and revealed that SK‑UT‑1B cells exhibited markedly greater sensitivity to TAK‑981 than SK‑UT‑1 cells. TAK‑981 substantially reduced SK‑UT‑1B cell viability in a time‑ and concentration‑dependent manner, whereas SK‑UT‑1 cells demonstrated a minimal response to TAK‑981 at similar doses. Annexin V staining confirmed that TAK‑981 induced the apoptosis of SK‑UT‑1B cells after 48 h, with apoptotic populations increasing proportionally with drug concentration. Furthermore, TAK‑981 induced G₀/G₁ cell cycle arrest and markedly decreased Ki67 expression, indicating suppressed proliferative activity. TAK‑981 also triggered substantial intracellular reactive oxygen species (ROS) accumulation and mitochondrial membrane depolarization, and antioxidant co‑treatment demonstrated that apoptosis was partially ROS‑dependent. Western blotting indicated robust inhibition of SUMO2/3 conjugation and activation of apoptotic markers, including cleaved caspase‑3 and poly (ADP‑ribose) polymerase, with the upregulation of p21 and p53. By contrast, autophagy markers, such as LC3B and p62, were unchanged, indicating that TAK‑981 exerted its cytotoxic effects independently of the autophagic pathway. Collectively, these findings suggested that TAK‑981 suppressed proliferation and induced apoptosis in SK‑UT‑1B Ut‑LMS cells, accompanied by SUMOylation inhibition, ROS‑associated mitochondrial dysfunction, apoptosis and G₀/G₁ cell‑cycle arrest, and may represent a promising therapeutic candidate for further investigation in Ut‑LMS.