ADR-directly-interfering amino acids based on competitive isoTOP-ABPP in normoxia

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most malignant tumors in the world with high morbidity and mortality rate. Many strategies have been tried to fight with HCC, yet effective treatment is still lacking. In this study, the in vitro and in vivo anti-HCC activity of andrographolide (ADR), an active ingredient of Andrographis Herba, has been demonstrated. We performed quantitative chemoproteomic profiling and identified heat shock protein HSP 90-alpha (HSP90AA1), an important molecular chaperone in endoplasmic reticulum protein processing, as the key target of ADR. The compound covalently bound to C597 and C598 therefore directly inhibited HSP90AA1 with isoform selectivity and reduced protein synthesis and triggered mitochondrial pathway-mediated apoptosis in HCC cancer cells collected in normoxia. Moreover, the inhibitory ability of ADR to HSP90AA1 was negatively correlated with the amount of this protein in cancer cells, and the mechanism was different from the existing inhibitors. Our study of ADR as a naturally derived and selective HSP90AA1 inhibitor provides new ideas for the treatment of HCC as well as other cancers.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: wei zhou  

LAB HEAD: Jianye Dai

PROVIDER: PXD034583 | Pride | 2023-03-11

REPOSITORIES: Pride