Research Paper Volume 11, Issue 15 pp 5769—5785

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

Jialiang Wang 1, *, , Huan Wei 1, *, , Yanlin Huang 2, , Dongmei Chen 1, , Guofen Zeng 2, , Yifan Lian 1, , Yuehua Huang 1, 2, ,

  • 1 Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
  • 2 Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
* Equal contribution

received: April 14, 2019 ; accepted: August 5, 2019 ; published: August 13, 2019 ;

https://doi.org/10.18632/aging.102165
How to Cite
This article has been corrected. See Correction. Aging (Albany NY). 2019; 11:7328-7328. https://doi.org/10.18632/aging.102289

Copyright © 2019 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Abbreviations

Lona: Lonafarnib; Sora: Sorafenib; CCK-8: Cell Counting Kit-8; DMSO: dimethyl sulfoxide; ECL: enhanced chemiluminescence; FBS: fetal bovine serum; HCC: hepatocellular carcinoma; PVDF: polyvinylidene fluoride; qRT-PCR: real-time quantitative PCR; DAPI: 4′,6-diamidino-2-phenylindole.