Proteasomal deubiquitinating enzyme USP14/UCHL5 inhibitor bAP15 suppresses endoplasmic reticulum stress-mediated apoptosis and tumor growth in human chondrosarcoma

Chondrosarcoma is a malignant bone tumor with limited systemic options. Here, using the small-molecule probe bAP15 to inhibit proteasome-associated deubiquitinating enzymes (DUBs) USP14 and UCHL5, we evaluated the therapeutic concept of DUB inhibition in human chondrosarcoma. Immunohistochemistry showed higher USP14/UCHL5 expression in chondrosarcoma than in normal cartilage controls. In vitro, bAP15 increased Annexin V/PI-positive apoptosis and cleavage of caspase-3/PARP. Under our experimental conditions (low sub-micromolar exposure, 24-48 h), bAP15 led to a predominant accumulation of cells in G1, accompanied by p21 upregulation and reduced PCNA and phospho-histone H3. bAP15 was associated with lower phosphorylation of AKT/ERK and with the induction of ER-stress markers (GRP78, CHOP, IRE1α, caspase-4). In vivo, bAP15 suppressed xenograft growth. Collectively, these data support proteasome-associated DUB inhibition as a potential strategy in chondrosarcoma, with bAP15 serving as a chemical tool to probe this target class.