Targeting glucose‐6‐phosphate dehydrogenase by 6‐AN induces ROS‐mediated autophagic cell death in breast cancer

• Published in: The FEBS journal 2023-02, Vol.290 (3), p.763-779
• Main Authors: Li, Yin, Zheng, Fangxu, Zhang, Yupeng, Lin, Zhoujun, Yang, Juan, Han, Xiao, Feng, Ya, Pei, Xiaolin, Li, Fei, Liu, Qiao, Yan, Lizhong, Li, Tianjiao, Zhang, Yifan, Li, Ding, Fu, Zhenkun, Wang, Changjun, Sun, Qiang, Li, Chenggang
• Format: Article
• Language: English
• Subjects: 6‐AN; Apoptosis; Autophagic Cell Death; Autophagy; Breast cancer; Breast Neoplasms - pathology; Cell death; Cell Line, Tumor; Cell migration; Cell Proliferation; Cell viability; Enzymatic activity; Enzyme activity; Female; G6PD; Gene expression; Glucose 6 phosphate dehydrogenase; Glucosephosphate dehydrogenase; Glucosephosphate Dehydrogenase - genetics; Humans; Molecular modelling; Mortality; Original; Patients; Pentose; Pentose phosphate pathway; Pentose Phosphate Pathway - physiology; PPP; Reactive Oxygen Species - metabolism; Tumorigenesis; Tumors
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16614

Dysregulation of G6PD involved in the pentose phosphate pathway (PPP) is known to promote tumorigenesis. The PPP plays a pivotal role in meeting the anabolic demands of cancer cells. However, the detailed underlying molecular mechanisms of targeting the G6PD‐regulated PPP in breast cancer remain unclear. In this study, we aimed to elucidate the molecular pathways mediating the effects of G6PD on cancer progression. Clinical sample analysis found that the expression of G6PD in breast cancer patients was higher than that in normal controls, and patients with higher G6PD expression had poor survival. Gene knockdown or inhibition of G6PD by 6‐AN in MCF‐7 and MDA‐MB‐231 cells significantly decreased cell viability, migration, and colony formation ability. G6PD enzyme activity was inhibited by 6‐AN treatment, which caused a transient upregulation of ROS. The elevated ROS was independent of cell apoptosis and thus associated with abnormal activated autophagy. Accumulated ROS levels induced autophagic cell death in breast cancer. Inhibition of G6PD suppresses tumour growth in preclinical models of breast cancer. Our results indicate that targeting the G6PD‐regulated PPP could restrain tumours in vitro and in vivo, inhibiting G6PD caused cell death by over‐activating autophagy, therefore leading to inhibited proliferation and tumour formation. Our research reveals that targeting abnormal elevated G6PD activity by 6‐AN in breast cancer, blocked the generation of NADPH, induced ROS accumulation, triggered autophagic cell death rather than apoptotic cell death, therefore exhibiting effective anti‐tumor function. This study provides a novel strategy for development of effective treatment in breast cancer.