Hyunju Liu

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

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.

Proteasome inhibition by bortezomib induces stress-response–mediated cytotoxicity in uterine leiomyosarcoma cells

Uterine leiomyosarcoma (Ut-LMS) is a rare and aggressive gynecologic malignancy with limited effective therapeutic options. In this study, we investigated the cytotoxic effects and underlying mechanisms of bortezomib in Ut-LMS cell lines SK-LMS-1 and SK-UT-1B. Bortezomib treatment significantly reduced cell viability and increased lactate dehydrogenase release, indicating pronounced cytotoxicity. Apoptotic cell death was induced, as evidenced by increased Annexin V-positive cell populations. Bortezomib also suppressed proliferative activity, reflected by reduced Ki67 expression, and induced G2/M cell cycle arrest in SK-LMS-1 cells, whereas SK-UT-1B cells exhibited minimal alterations in cell cycle distribution. In addition, bortezomib increased reactive oxygen species production in SK-UT-1B cells and induced mitochondrial membrane depolarization in both cell lines, while antioxidant treatment attenuated bortezomib-induced apoptosis in SK-UT-1B cells, indicating partial involvement of oxidative stress. Western blot analysis further revealed enhanced cleavage of poly(ADP-ribose) polymerase and caspase-3, along with modulation of cell cycle regulatory proteins, including upregulation of p21 and differential regulation of p53 between the two cell lines. Finally, autophagy-related analyses demonstrated increased LC3B-II levels accompanied by p62 accumulation, suggesting altered autophagic processing rather than simple activation of autophagy. Collectively, these findings demonstrate that bortezomib exerts cytotoxic effects in Ut-LMS cells through coordinated regulation of proteasome inhibition-associated apoptosis, cell cycle control, mitochondrial dysfunction, and autophagy-related signaling, with cell line-specific differences in stress response pathways.