Polyphyllin I activates AMPK to suppress the growth of non-small-cell lung cancer via induction of autophagy.

Abstract:

:Polyphyllin I (PPI), a bioactive constituent extracted from the rhizomes of Paris polyphylla, is cytotoxic to several cancer types. This study was designed to explore whether PPI prevents non-small-cell lung cancer (NSCLC) growth and to investigate the molecular mechanism. AMP-activated protein kinase (AMPK) has been implicated in the activation of autophagy in distinct tissues. In cultured human NSCLC cell lines, PPI induces autophagy by activating AMPK and then inhibiting mTOR signaling in a concentration-dependent manner. Furthermore, the activation of autophagy induced by PPI was reversed by the AMPK inhibitor compound C. Computational docking showed that PPI directly interacted with the allosteric drug and metabolite site of AMPK to stabilize its activation. Microscale thermophoresis and Drug Affinity Responsive Targeting Stability (DARTS) assay further confirmed the high affinity between PPI and AMPK. In vivo studies indicated that PPI suppressed the growth of NSCLC and increased the levels of LC3-II and phosphorylated AMPK in tumors isolated from a xenograft model of NSCLC in mice. Moreover, PPI exhibited favorable pharmacokinetics in rats. In summary, PPI conclusively acts as a direct AMPK activator to induce cell autophagy which inhibits the growth of NSCLC cells. In the future, PPI therapy should be applied to treat patients with NSCLC.

journal_name

Arch Biochem Biophys

authors

Wu Y,Si Y,Xiang Y,Zhou T,Liu X,Wu M,Li W,Zhang T,Xiang K,Zhang L,Zhao H,Liu Y

doi

10.1016/j.abb.2020.108285

subject

Has Abstract

pub_date

2020-07-15 00:00:00

pages

108285

eissn

0003-9861

issn

1096-0384

pii

S0003-9861(19)30990-7

journal_volume

687

pub_type

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