Mcl-1-dependent activation of Beclin 1 mediates autophagic cell death induced by sorafenib and SC-59 in hepatocellular carcinoma cells
Open accessAbstract
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.
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Sorafenib activates autophagy in multiple liver cancer cell lines through targeting STAT3 and reducing MCL1 expression.
“Sorafenib, a small-molecule kinase insert domain receptor inhibitor, activates autophagy in multiple liver cancer cell lines through targeting STAT3 and reducing MCL1 expression (Tai et al., 2013).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Tai et al., 2013
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- Authors
- Tai, W.-T., Shiau, C.-W., Chen, H.-L., Liu, C.-Y., Lin, C.-S., Cheng, A.-L., Chen, P.-J., & Chen, K.-F.
- Affiliations
- National Taiwan University Hospital (TW)
- National Yang Ming University (TW)
- Taipei Veterans General Hospital (TW)
- National Taiwan University (TW)
- Corresponding author
- Chen, K-F
- Venue
- Cell Death & Disease
- Published
- 2013-02-07
- Volume
- 4
- Issue
- 2
- Pages
- e485-e485
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC3734819
- OpenAlex
- W2076745136
- Cited by
- 202
- References
- 43
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 15 · 2023: 13 · 2022: 10 · 2021: 20 · 2020: 21 · 2019: 16 · 2018: 24 · 2017: 19 · 2016: 12 · 2015: 17 · 2014: 16 · 2013: 7
- FWCI
- 12.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Cell Death and Disease (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Science Council (100-2325-B-002 -032)
- National Taiwan University Hospital (NTUH 101P01)
- National Taiwan University
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- sorafenib, hepatocellular carcinoma, autophagy, autophagic cell death, Beclin-1, Mcl-1, STAT3, SHP-1, anticancer agents
- MeSH terms
- Beclin-1, Sorafenib, Animals, Antineoplastic Agents, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Membrane Proteins, Mice, Nude, Niacinamide, Phenylurea Compounds, Phosphorylation, Transplantation, Heterologous, Down-Regulation, Apoptosis, Proto-Oncogene Proteins c-bcl-2, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, STAT3 Transcription Factor, Apoptosis Regulatory Proteins, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Hep G2 Cells, Myeloid Cell Leukemia Sequence 1 Protein
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