The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells
Identifieur interne : 000350 ( Main/Exploration ); précédent : 000349; suivant : 000351The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells
Auteurs : Jialiang Wang [République populaire de Chine] ; Huan Wei [République populaire de Chine] ; Yanlin Huang [République populaire de Chine] ; Dongmei Chen [République populaire de Chine] ; Guofen Zeng [République populaire de Chine] ; Yifan Lian [République populaire de Chine] ; Yuehua Huang [République populaire de Chine]Source :
- Aging (Albany NY) [ 1945-4589 ] ; 2019.
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.
Url:
DOI: 10.18632/aging.102165
PubMed: 31409760
PubMed Central: 6710066
Affiliations:
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when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>République populaire de Chine</li></country><region><li>Guangdong</li></region><settlement><li>Jiangmen</li></settlement></list><tree><country name="République populaire de Chine"><region name="Guangdong"><name sortKey="Wang, Jialiang" sort="Wang, Jialiang" uniqKey="Wang J" first="Jialiang" last="Wang">Jialiang Wang</name></region><name sortKey="Chen, Dongmei" sort="Chen, Dongmei" uniqKey="Chen D" first="Dongmei" last="Chen">Dongmei Chen</name><name sortKey="Huang, Yanlin" sort="Huang, Yanlin" uniqKey="Huang Y" first="Yanlin" last="Huang">Yanlin Huang</name><name sortKey="Huang, Yuehua" sort="Huang, Yuehua" uniqKey="Huang Y" first="Yuehua" last="Huang">Yuehua Huang</name><name sortKey="Huang, Yuehua" sort="Huang, Yuehua" uniqKey="Huang Y" first="Yuehua" last="Huang">Yuehua Huang</name><name sortKey="Lian, Yifan" sort="Lian, Yifan" uniqKey="Lian Y" first="Yifan" last="Lian">Yifan Lian</name><name sortKey="Wei, Huan" sort="Wei, Huan" uniqKey="Wei H" first="Huan" last="Wei">Huan Wei</name><name sortKey="Zeng, Guofen" sort="Zeng, Guofen" uniqKey="Zeng G" first="Guofen" last="Zeng">Guofen Zeng</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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