Hemistepsin a inhibits cell proliferation and induces g0/g1-phase arrest, cellular senescence and apoptosis via the ampk and p53/p21 signals in human hepatocellular carcinoma

Su Youn Baek, Ui Wook Hwang, Ho Young Suk, Young Woo Kim

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20 Scopus citations

Abstract

Hemistepsin A (HsA), a natural sesquiterpene lactone isolated from Hemistepta lyrata, has been known as a wide range of anti-tumor effects. The aim of this study was to determine whether HsA suppresses hepatocellular carcinoma (HCC) and to figure out the cellular signaling pathways involved in the anti-HCC activities by experiments using the Huh7 cells (a human HCC cell line) and a xenograft HCC model. In this study, HsA completely inhibited HCC cell proliferation, presumably because it induced G0/G1 cell cycle arrest and mitochondrial-related apoptosis. HsA up-regulated p53, p21, cleaved caspase-3 and cleaved PARP (poly (ADP-ribose) polymerase), but reduced cyclin D, CDK6 and Bcl-2 expressions, and it disrupted mitochondrial membrane potential (ΔΨm). Moreover, phosphorylation of AMP-activated protein kinase (AMPK) was increased by HsA as did the resveratrol and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR, positive controls). Inhibition of AMPK by using compound C, a competent inhibitor of AMPK, attenuated the loss of ΔΨm, p53 up-regulation and cellular senescence. The efficacy of HsA to reduce HCC cell proliferation, compared to that of other known anti-HCC agents, appears to be similar or slightly better. The anti-tumor effect of HsA was also determined in mice, showing reduced growth of xenografted tumors with no weight loss. Overall, the results suggest that HsA should be considered as a candidate anti-HCC drug.

Original languageEnglish
Article number713
JournalBiomolecules
Volume10
Issue number5
DOIs
StatePublished - May 2020

Keywords

  • AMP-activated protein kinase (AMPK/mTOR)
  • Apoptosis
  • G0/G1 cell cycle arrest
  • Hemistepsin A (HsA)
  • Hepatocellular carcinoma (HCC)
  • P53

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