ULK1 promotes oxaliplatin resistance of colon cancer via phosphorylation of Bax S184
Menée à l'aide de lignées cellulaires, de xénogreffes sur des modèles murins, d'échantillons tumoraux de patients atteints d'un cancer du côlon et de données du programme "The Cancer Genome Atlas", cette étude met en évidence un mécanisme par lequel la kinase ULK1 favorise la résistance des cellules cancéreuses à l'oxaliplatine via la phosphorylation de la sérine s184 de la protéine Bax
Background : Oxaliplatin resistance continues to undermine therapeutic outcomes in colon cancer (CC). Recent investigations point to unc-51 like kinase 1 (ULK1)-mediated disruption of apoptotic pathways as a potential driver of chemoresistance, though the exact mechanisms remain incompletely characterized.
Methods : Using established CC cell lines, we developed oxaliplatin-resistant models through stepwise dose escalation. ULK1 expression was modulated through targeted siRNA knockdown and stable overexpression. Protein interactions were examined via co-immunoprecipitation coupled with mass spectrometry, supplemented by kinase activity assays. Functional impact was assessed through proliferation kinetics, apoptosis profiling, and tumor xenograft studies. Clinical correlations were derived from TCGA analysis and immunohistochemical evaluation of patient tumor specimens.
Results : ULK1 overexpression consistently correlated with oxaliplatin resistance and adverse clinical parameters. At the molecular level, ULK1 catalyzed Bcl-2 associated X protein (Bax) phosphorylation at Ser184, creating a recognition motif for Parkin-mediated ubiquitination and proteasomal targeting. Disruption of this axis through ULK1 inhibition restored Bax protein levels, enhanced apoptotic response, and reversed oxaliplatin resistance in both cellular and animal models.
Conclusion : These findings identify ULK1-dependent phosphorylation as a novel regulatory mechanism governing Bax stability in CC. The study provides preclinical rationale for targeting the ULK1-Bax interface to overcome oxaliplatin resistance, while highlighting the need for further investigation into optimal therapeutic strategies.
British Journal of Cancer , article en libre accès, 2026