TAK-981 enhances antitumor activity in ELT3 uterine leiomyoma cells through the modulation of apoptosis, cell cycle arrest, and autophagy

Abstract

Uterine leiomyomas, commonly known as fibroids, are the most prevalent benign tumors in women of reproductive age and are characterized by abnormal smooth muscle cell proliferation in the uterine wall. TAK-981 (subasumstat), an investigational drug that inhibits SUMOylation by targeting SUMO-activating enzymes, has demonstrated high potential for the treatment of various cancers. However, its effects on uterine leiomyomas remain largely unexplored. In this study, we evaluated the therapeutic effects of TAK-981 on ELT3 uterine leiomyoma cells. TAK-981 significantly decreased the viability of ELT3 uterine leiomyoma cells and inhibited colony formation. It also induced apoptosis and caused G2/M phase cell cycle arrest, demonstrating a strong effect on cell proliferation and survival. Notably, although TAK-981 enhances reactive oxygen species production, it also induces apoptosis through a reactive oxygen species-independent mechanism, as evidenced by increased apoptosis rates upon co-treatment with antioxidants such as N-acetylcysteine. Furthermore, western blot analysis revealed that treatment with TAK-981 downregulated MEK-1 expression and inhibited ERK phosphorylation, leading to enhanced cleavage of caspase-3 and PARP, thereby promoting apoptosis in ELT3 cells. Additionally, TAK-981 reduced extracellular matrix accumulation by suppressing Collagen I and Acta2 expression and promoted autophagy in ELT3 cells, as indicated by increased levels of LC3. These findings suggest that TAK-981 can be used as a therapeutic option for managing uterine leiomyomas through multiple mechanisms, including apoptosis induction and autophagy promotion.

Keywords: Antitumor; Fibroid; Leiomyoma; TAK-981; Uterine.