Translational cancer research · 2026
ALOX12 suppresses colon cancer progression by promoting p53-mediated ferroptosis through upregulating ROS-induced stress.
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Wu Junjie, Liu Congxing, Sun Yaya, Jiang Guangqing, Zhao Yupeng, Zhang Yihong, Yin Yiping, Shi Xin
Аннотация
BACKGROUND: Colon cancer (CC) is a heterogeneous disease with increasing morbidity and mortality. Ferroptosis, a recently identified form of regulated cell death (RCD) characterized by the massive accumulation of iron-dependent lipid peroxidation (LPO), has been proven to be closely associated with various biological behaviors of CC. Moreover, accumulating evidence reveals that ALOX12 is essential for p53-mediated ferroptosis through distinct pathways. Therefore, our study aims to explore the specific mechanisms by which ALOX12 regulates tumorigenesis in CC through ferroptosis pathway.
METHODS: We explored the characteristics of ALOX12 expression and its correlation with prognosis in CC patients and cell lines, followed by a series of functional assays in vitro and in vivo to investigate the mechanisms underlying the functions of ALOX12 in p53-driven ferroptosis.
RESULTS: We discovered that ALOX12 was downregulated in CC tissues and cell lines, which was correlated with poor prognosis. Furthermore, overexpression of ALOX12 suppressed cell proliferation and tumorigenesis by upregulating reactive oxygen species (ROS)-induced stress. We continuously found that increased ALOX12 levels enhanced the sensitivity of CC cells to a distinct ferroptosis, which required both p53 activation and additional ROS, and differed from that induced by erastin.
CONCLUSIONS: Our study demonstrates the oncosuppressive behavior of ALOX12 in CC. Mechanistically, we discover that p53 can indirectly activate ALOX12 function by suppressing its transcriptional target SLC7A11, resulting in an ALOX12-dependent ferroptotic pathway. Targeting ALOX12 may provide a novel biomarker or new therapeutic strategies for improving the prognosis of CC.
METHODS: We explored the characteristics of ALOX12 expression and its correlation with prognosis in CC patients and cell lines, followed by a series of functional assays in vitro and in vivo to investigate the mechanisms underlying the functions of ALOX12 in p53-driven ferroptosis.
RESULTS: We discovered that ALOX12 was downregulated in CC tissues and cell lines, which was correlated with poor prognosis. Furthermore, overexpression of ALOX12 suppressed cell proliferation and tumorigenesis by upregulating reactive oxygen species (ROS)-induced stress. We continuously found that increased ALOX12 levels enhanced the sensitivity of CC cells to a distinct ferroptosis, which required both p53 activation and additional ROS, and differed from that induced by erastin.
CONCLUSIONS: Our study demonstrates the oncosuppressive behavior of ALOX12 in CC. Mechanistically, we discover that p53 can indirectly activate ALOX12 function by suppressing its transcriptional target SLC7A11, resulting in an ALOX12-dependent ferroptotic pathway. Targeting ALOX12 may provide a novel biomarker or new therapeutic strategies for improving the prognosis of CC.