Abstract
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.
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Acknowledgements
The authors would like to thank Prof. Yue Chen and Mrs. Xue-mei Zhang for instructing ACT001 treatment and generously providing ACT001-biotin and ACT001-S-biotin probes. This work was supported by Zhejiang Provincial Natural Science Foundation of China (Grants No. LY19C070002 to ZPS and Grants No. LY22H160016 to ZRW), Key Research Project of Traditional Chinese Medicine of Zhejiang Province of China (Grants No. 2019ZZ015 to ZPS), Medical Health Science and Technology Research Project of Zhejiang Province of China (Grants No. 2018KY515 to CDW), and Science and Technology Project of Wenzhou City of China (Grants No. Y2020061 to JLL).
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LC: Conceptualization, methodology, investigation, and writing-original draft. ZRW: Methodology, writing-review and editing, supervision, funding acquisition. LC: Conceptualization, methodology, and investigation. JDX: Conceptualization, methodology, and investigation. JLL: Methodology, supervision, and investigation. CDW: Supervision, investigation. JHJ: Supervision, investigation. ZBW: Conceptualization, writing-review and editing, supervision. ZPS: Conceptualization, writing-review and editing, supervision, funding acquisition.
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Cai, L., Wu, Zr., Cao, L. et al. ACT001 inhibits pituitary tumor growth by inducing autophagic cell death via MEK4/MAPK pathway. Acta Pharmacol Sin 43, 2386–2396 (2022). https://doi.org/10.1038/s41401-021-00856-5
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DOI: https://doi.org/10.1038/s41401-021-00856-5
