Carcinogenesis. 2025 Jul 20:bgaf035. doi: 10.1093/carcin/bgaf035. Online ahead of print.
ABSTRACT
L-asparaginase (L-ASP) is an important chemotherapeutic agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, resistance to L-ASP is an unfavorable prognostic factor and the mechanism underlying L-ASP resistance is not fully understood. Here, we show that activation of the activating transcription factor 4 (ATF4) and induced expression of downstream target asparagine synthetase (ASNS) play a pivotal role in L-ASP resistance of ALL cells. In addition, the G protein pathway suppressor 2 (GPS2) binds to ATF4 and stabilizes ATF4 protein. Mechanistically, GPS2 inhibits ubiquitin-proteasome degradation of ATF4 through impairing the interaction between ATF4 and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC), an E3 ligase that triggers proteasomal degradation of ATF4. Moreover, GPS2 knockdown sensitizes ALL cells to L-ASP treatment via repressing ATF4/ASNS axis in vitro and increases L-ASP efficacy against xenografted ALL tumors in vivo. Taken together, these findings demonstrate that GPS2 positively regulates ATF4/ASNS axis to confer L-ASP resistance in ALL cells, suggesting a therapeutic potential of targeting this pathway to overcome L-ASP resistance.
PMID:40693356 | DOI:10.1093/carcin/bgaf035
