2. Academic Validation
  3. AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis

AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis

  • Sci China Life Sci. 2024 Sep 6. doi: 10.1007/s11427-023-2589-1.
Chen Xiong # 1 2,  Hong Ling # 2 3,  Yingdan Huang 1 2,  Hanzhi Dong 4,  Bangxiang Xie 5 6,  Qian Hao 7 8,  Xiang Zhou 9 10 11 12
Affiliations

Affiliations

  • 1 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 3 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
  • 4 Department of Oncology, First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
  • 5 Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
  • 6 Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing, 100069, China.
  • 7 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. haoqian@fudan.edu.cn.
  • 8 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. haoqian@fudan.edu.cn.
  • 9 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. xiangzhou@fudan.edu.cn.
  • 10 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. xiangzhou@fudan.edu.cn.
  • 11 Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. xiangzhou@fudan.edu.cn.
  • 12 Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. xiangzhou@fudan.edu.cn.
  • # Contributed equally.
PMID: 39245684 DOI: 10.1007/s11427-023-2589-1
Abstract

Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against Cancer therapies, including Wee1 inhibition. Considering that p53 activation can also lead to multiple types of cell death, the role of this tumor suppressor in Wee1 inhibitor-based therapies remains disputed. In this study, we reported that nucleolar stress-mediated p53 activation enhanced the Wee1 Inhibitor AZD1775-induced Ferroptosis to suppress lung Cancer growth. Our findings showed that AZD1775 promoted Ferroptosis by blocking cystine uptake, an action similar to that of Erastin. Meanwhile, inhibition of Wee1 by the Wee1 inhibitors or siRNAs induced compensatory upregulation of SLC7A11, which conferred resistance to Ferroptosis. Mechanistically, AZD1775 prevented the enrichment of H3K9me3, a histone marker of transcriptional repression, on the SLC7A11 promoter by repressing the expression of the Histone Methyltransferase SETDB1, thereby enhancing NRF2-mediated SLC7A11 transcription. This finding was also validated using the H3K9me3 inhibitor BRD4770. Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D (Act. D) inhibited SLC7A11 expression by activating p53, thus augmenting AZD1775-induced Ferroptosis. Moreover, the combination of AZD1775 and Act. D synergistically suppressed wild-type p53-harboring lung Cancer cell growth both in vitro and in vivo. Altogether, our study demonstrates that AZD1775 promotes Ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing Ferroptosis in cancers with wild-type p53.

Keywords

AZD1775; NRF2; SLC7A11; WEE1; ferroptosis; nucleolar stress; p53.

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