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.

MiR-139-5p influences hepatocellular carcinoma cell invasion and proliferation capacities via decreasing SLITRK4 expression

“…Every year, the government has provided millions of money to the studies of HCC, and sorafenib and regorafenib have made great contributions for the therapy of HCC. What's more, many studies have focused the mechanisms of HCC progression and metastasis [26][27][28][29]. Our study based on the clinical samples databases, and identified a new pathway connected to the progression of HCC, is another sample to study HCC progression for better therapy of HCC patients.…”

Mechanistic Insights about Sorafenib-, Valproic Acid- and Metformin-Induced Cell Death in Hepatocellular Carcinoma

“…In HCC, it was shown that the molecular mechanisms by which sorafenib induces autophagy could be independent of AMP-activated protein kinase (AMPK) and involve a reduction in MCL-1 levels, which in turns would inactivate signal transducer and activator of transcription 3 factor (STAT3), causing the accumulation of beclin-1 (BECN-1) and other proteins indicating autophagosome formation, such as LC3B-II accumulation, as well as sequestosome 1 (p62) reduction [25,28,41,49,73]. Several studies reported a dosedependent cytotoxic effect of sorafenib, along with the induction of the assembly of the autophagolysosome, which was accompanied by reduced cell viability and an increase in annexinV/Pi-positive cells in vitro, as well as by an increase in LC3-II conversion and autophagosome formation in tumor samples and a reduced tumor burden in HCC-bearing mice [37,41,74].…”

APEX1 is a novel diagnostic and prognostic biomarker for hepatocellular carcinoma

“…We analyzed the correlation between APEX1expression and drug resistance in HCC patients. Sorafenib is the gold standard main chemotherapeutic drug for treating advanced stage HCC patients, but its efficacy is affected by drug resistance [28]. We evaluated the correlation between APEX1 and sorafenib-resistance in HCC patients from the GSE109211 database.…”

“…reported in the United States [32]. Sorafenib is the only FDA-approved chemotherapeutic drug for advanced stage HCC [28]. There is an urgent need for novel therapeutic options for HCC to overcome the poor survival outcomes because of fewer effective drugs, chemotherapeutic resistance, and radiation toxicity.…”