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

Acta Pharmacol Sin. 2022 Sep;43(9):2386-2396. doi: 10.1038/s41401-021-00856-5. Epub 2022 Jan 26.

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.

Keywords: ACT001; JNK; MEK4; P38; autophagic cell death; pituitary adenoma.

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Apoptosis
  • Autophagic Cell Death*
  • Autophagy
  • Cell Line, Tumor
  • Furans
  • Humans
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinases / pharmacology
  • Pituitary Neoplasms* / drug therapy

Substances

  • ACT001
  • Antineoplastic Agents
  • Furans
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human