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Abstract
We investigated the molecular mechanisms underlying the effect of sorafenib and SC-59, a novel sorafenib derivative, on hepatocellular carcinoma (HCC). Sorafenib activated autophagy in a dose- and time-dependent manner in the HCC cell lines PLC5, Sk-Hep1, HepG2 and Hep3B. Sorafenib downregulated phospho-STAT3 (P-STAT3) and subsequently reduced the expression of myeloid cell leukemia-1 (Mcl-1). Inhibition of Mcl-1 by sorafenib resulted in disruption of the Beclin 1-Mcl-1 complex; however, sorafenib did not affect the amount of Beclin 1, suggesting that sorafenib treatment released Beclin 1 from binding with Mcl-1. Silencing of SHP-1 by small interference RNA (siRNA) reduced the effect of sorafenib on P-STAT3 and autophagy. Ectopic expression of Mcl-1 abolished the effect of sorafenib on autophagy. Knockdown of Beclin 1 by siRNA protected the cells from sorafenib-induced autophagy. Moreover, SC-59, a sorafenib derivative, had a more potent effect on cancer cell viability than sorafenib. SC-59 downregulated P-STAT3 and induced autophagy in all tested HCC cell lines. Furthermore, our in vivo data showed that both sorafenib and SC-59 inhibited tumor growth, downregulated P-STAT3, enhanced the activity of SHP-1 and induced autophagy in PLC5 tumors, suggesting that sorafenib and SC-59 activate autophagy in HCC. In conclusion, sorafenib and SC-59 induce autophagy in HCC through a SHP-1-STAT3-Mcl-1-Beclin 1 pathway.
Highlights
Administration for the treatment of advanced Hepatocellular carcinoma (HCC) in 2007, and is the first clinically approved targeted drug therapy for HCC.[9,10] the precise mechanism by which sorafenib induces tumor cell death is still under investigation
In the four HCC cell lines tested, we found significant induction of LC3-II with sorafenib at a clinically relevant dose indicating that sorafenib increases autophagosome formation in HCC cell lines (Figure 1a)
We validated the effect of sorafenib on autophagy by measuring: (1) the conversion of the cytoplasmic form of LC3 (LC3-I) to preautophagosomal/autophagosomal membrane-bound LC3 (LC3-II); (2) the autophagic degradation of p62; (3) electron microscopy of autophagosomes and (4) acridine orange (AO) staining to monitor acidic vesicular organelles (AVOs)
Summary
Administration for the treatment of advanced HCC in 2007, and is the first clinically approved targeted drug therapy for HCC.[9,10] the precise mechanism by which sorafenib induces tumor cell death is still under investigation. The process of mammalian autophagy is divided into six principal steps: initiation, nucleation, elongation, closure, maturation and degradation.[16,18] In addition to degradation thorough lysosomal machinery, autophagy has been reported to induce programmed cell death called autophagic cell death (ACD, programmed cell death type II).[19,20,21] Beclin 1 (Atg6), a Bcl-2-homology domain 3 (BH3) protein, interacts with Vps[34] (a class III PI3K), Vps[15] (a myristoylated kinase) and UV irradiation resistance-associated tumor suppressor gene (UVRAG) to form a core complex to allow autophagosome nucleation, a vital step of autophagy.[22] Bcl-2 and Keywords: SC-59; sorafenib; STAT3; HCC. Using a kinase-independent derivative of sorafenib, SC-59, we confirmed that this autophagic effect is related to the SHP-1/STAT3 signaling pathway Both SC-59 and sorafenib resulted in disassociation of the Mcl-1–Beclin 1 complex and induced autophagic cell death in vitro and in vivo via a SHP-1/STAT3-dependent mechanism
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