Abstract High CDX2 expression frequently indicates better survival in stage II-III colon cancer; nevertheless, it is linked to decreased systemic chemotherapy response rates. Ferroptosis, commonly recognized as an iron-dependent oxidative death, is increasingly believed as a disease-modifying mechanism. The purpose of this study is to determine the role of ferroptosis in CDX2-mediated colon cancer chemical resistance. Mechanistically, CDX2-mediated NUPR1 transcription prevents ferroptotic cell death by reducing iron accumulation and oxidative stress damage. Depletion of NUPR1 counteracted the effect of CDX2 overexpression in terms of ferroptosis resistance, whereas transfection-enforced re-expression of NUPR1 restores ferroptosis resistance in CDX2-deficient cells. Genetic or pharmacological blockage of CDX2-NUPR1 axis improved the potential of ferroptosis agonists to combat colon cancer in preclinical mouse models. Our study uncovered a novel molecular mechanism by which CDX2 imparts ferroptosis resistance to colon cancer. Blockage of NUPR1 might be as a potential therapeutic strategy for CDX2-positive stage II-III colon cancer.
Yu et al. (Thu,) studied this question.