The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells.

Abstract:

:Combination treatment is a promising strategy to improve prognosis of hepatocellular carcinoma (HCC). Sorafenib is a traditional first-line agent approved for the treatment of advanced HCC, though with limited efficacy. Previously, we reported that lonafarnib, an orally bioavailable non-peptide inhibitor targeting farnesyltransferase, synergizes with sorafenib against the growth of HCC cells. In the present study, we aim to clarify the underlying mechanism of this combination strategy. Initially, using in vitro HCC cell model, we confirmed that synergistic treatment of lonafarnib and sorafenib suppressed cell viability and colony formation, and induced cell death. We then found conversion of LC3-I to LC3-II via combination the treatment and observed formation of autophagosomes by electron microscopy. Knockdown of ATG3 inhibited the autophagic flux induced by the combination treatment. Furthermore, we demonstrated that drug-eliciting autophagy selectively promoted the degradation of cyclin D1 in a lysosome-dependent manner and subsequently inhibited DNA synthesis through downregulating the phosphorylation of Rb protein. In conclusion, our results provide a deeper insight into the mechanism for the combination treatment of lonafarnib and sorafenib in HCC therapy.

journal_name

Aging (Albany NY)

journal_title

Aging

authors

Wang J,Wei H,Huang Y,Chen D,Zeng G,Lian Y,Huang Y

doi

10.18632/aging.102165

subject

Has Abstract

pub_date

2019-08-13 00:00:00

pages

5769-5785

issue

15

issn

1945-4589

pii

102165

journal_volume

11

pub_type

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