2. Academic Validation
  3. MCL restrained ROS/AKT/ASAH1 pathway to therapy tamoxifen resistance breast cancer by stabilizing NRF2

MCL restrained ROS/AKT/ASAH1 pathway to therapy tamoxifen resistance breast cancer by stabilizing NRF2

  • Cell Prolif. 2024 Jun 26:e13700. doi: 10.1111/cpr.13700.
Xiao Han 1 2 3,  Yupeng Zhang 3,  Yin Li 3,  Zhoujun Lin 3,  Zhenkun Fu 4,  Changjun Wang 5,  Shengjie Zhang 1 2,  Di Shao 6 7,  Chenggang Li 3
Affiliations

Affiliations

  • 1 Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
  • 2 Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China.
  • 3 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.
  • 4 Department of Immunology & Wu Lien-Teh Institute & Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University & Heilongjiang Academy of Medical Science, Harbin, China.
  • 5 Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China.
  • 6 Chonggang General Hospital, Chongqing, China.
  • 7 Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing, China.
PMID: 38924190 DOI: 10.1111/cpr.13700
Abstract

Tamoxifen resistance is a common and difficult problem in the clinical treatment of breast Cancer (BC). As a novel antitumor agent, Micheliolide (MCL) has shown a better therapeutic effect on tumours; however, little is known about MCL and its role in BC therapy. With tamoxifen stimulation, drug-resistant BC cells MCF7TAMR and T47DTAMR obtained a high oxidative status and Amidohydrolase 1 (ASAH1) was abnormally activated. The inhibition of ASAH1 rescued the sensitivity of resistant cells to tamoxifen. We found that MCL inhibited the expression of ASAH1 and cell proliferation, especially in MCF7TAMR and T47DTAMR cells. The high oxidative stress status of resistant cells stimulated the expression of ASAH1 by positively regulating Akt, which was restrained by MCL. MCL activated NRF2 by directly binding to KEAP1 and promoting the antioxidant level of tamoxifen-resistant (TAMR) cells. In addition, ACT001, the prodrug of MCL, significantly inhibited the tumour growth of TAMR cells in preclinical xenograft tumour models. In conclusion, ASAH1 mediates tamoxifen resistance in ER-positive BC cells. MCL could activate the cellular antioxidant system via NRF2/KEAP1 and inhibit ASAH1 expression through the ROS/Akt signalling pathway, thus suppressing cell proliferation. MCL could be used as a potential treatment for TAMR-BC.

Figures
Products