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.