ACT001 inhibits pituitary tumor growth by inducing autophagic cell death via MEK4/MAPK pathway

Lin Cai1, Ze-rui Wu1, Lei Cao2, Jia-dong Xu3, Jiang-long Lu1, Cheng-de Wang1, Jing-hao Jin1, Zhe-bao Wu1,4, Zhi-peng Su1
1 Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
3 Department of Cardio‐Thoracic Surgery, Zhoushan Hospital, Zhoushan 316021, China
4 Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Correspondence to: Zhe-bao Wu:, Zhi-peng Su:,
DOI: 10.1038/s41401-021-00856-5
Received: 21 September 2021
Accepted: 27 December 2021
Advance online: 26 January 2022


ACT001, derived from traditional herbal medicine, is a novel compound with effective anticancer activity in clinical trials. However, little is known regarding its role in pituitary adenomas. Here, we demonstrated that ACT001 suppressed cell proliferation and induced cell death of pituitary tumor cells in vitro and in vivo. ACT001 was also effective in suppressing the growth of different subtypes of human pituitary adenomas. The cytotoxic mechanism ACT001 employed was mainly related to autophagic cell death (ACD), indicated by autophagosome formation and LC3-II accumulation. In addition, ACT001-mediated inhibitory effect decreased when either ATG7 was downregulated or cells were cotreated with autophagy inhibitor 3-methyladenine (3-MA). RNA-seq analysis showed that mitogen-activated protein kinase (MAPK) pathway was a putative target of ACT001. Specifically, ACT001 treatment promoted the phosphorylation of JNK and P38 by binding to mitogen-activated protein kinase kinase 4 (MEK4). Our study indicated that ACT001-induced ACD of pituitary tumor cells via activating JNK and P38 phosphorylation by binding with MEK4, and it might be a novel and effective anticancer drug for pituitary adenomas.
Keywords: ACT001; pituitary adenoma; autophagic cell death; MEK4; P38; JNK

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