Role of ferroptosis in hepatocellular carcinoma
- 1.2k Downloads
Hepatocellular carcinoma (HCC) is a complicated disease with low survival rate due to frequent recurrence and the lack of efficient therapies. For advanced HCC, sorafenib, as the only approved first-line drug for HCC, improves the survival to some extent, but depressingly with severe adverse effects and emerging resistance conditions, which cause a poor prognosis. Ferroptosis is a new recognized way of non-apoptosis-regulated cell death, characterized by the iron-dependent accumulation of lipid hydroperoxides, showing a tremendous promising in the therapy of cancer, especially in HCC. To provide ideas for the diagnosis and treatment of HCC, we summarized the role of ferroptosis in HCC.
The relevant literature from PubMed is reviewed in this article.
Interestingly enough, investigators have found sorafenib can induce ferroptosis in HCC. Moreover, recent researches reported increasing pathways and mechanisms related to ferroptosis in HCC such as TP53 and Rb, and strategies to improve sorafenib resistance by targeting ferroptosis. In addition, other drugs were reported to induce ferroptosis in HCC such as erastin and showed good efficacy in vivo and in vitro.
In this review, we summarize pathways and mechanisms of ferroptosis in HCC and other digestive system neoplasms such as gastric cancer, pancreatic cancer and colorectal cancer and point out the trends of ferroptosis in HCC.
KeywordsHepatocellular carcinoma Ferroptosis Sorafenib Lipid metabolism Iron Therapy
Regulated cell death
Nuclear factor erythroid 2-related factor 2
Ribosomal protein L8
Iron-responsive element-binding protein 2
ATP synthase F0 complex subunit C3
Tetratricopeptide repeat domain 35
Acyl-CoA synthetase family member 2
Reactive oxygen species
Glutathione peroxidase 4
Diffuse large B-cell lymphoma
Renal cell carcinoma
Kelch-like ECH-associated protein 1
V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog
Quinone oxidoreductase 1
Ferritin heavy chain 1
Hypoxia-inducible factor 1-alpha
Sigma 1 receptor
CDGSH iron sulfur domain 1
Acyl-CoA synthetase long-chain family member 4
Low-density lipoprotein docosahexaenoic acid
Cysteine dioxygenase 1
Pancreatic ductal adenocarcinoma
Heatshock 70-kDa protein 5
Nuclear receptor coactivator 4
Tumor necrosis factor-related apoptosis-inducing ligand
We are grateful to the staff at the GI oncology of cancer hospital of HMU. And we thank Kainan Kang for his critical reading of the manuscript.
This study was funded by the National Natural Scientific Foundation of China (No. 81302060, No.81472322 and No. 81672930), the national youth talent support program for TS Zheng, the Natural Science Foundation of Heilongjiang Province (LC201437/H1617), China Postdoctoral Science Foundation (No. 2015T80369 and No. 2014M560271), and Heilongjiang Postdoctoral Science Foundation (No. LBH-Z14142 and No. LBH-TZ1615), the Fok Ying Tung Education Foundation (No. 151037), the Academician Yu Weihan Outstanding youth foundation of Harbin Medical University for TS Zheng. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Compliance with ethical standards
Conflict of interest
Authors declare no conflict of interests.
This article does not contain any studies with human participants or animals performed by any of the authors.
- Arlt A et al (2013) Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene 32:4825–4835. https://doi.org/10.1038/onc.2012.493 CrossRefPubMedGoogle Scholar
- Cheng AL et al (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10:25–34. https://doi.org/10.1016/s1470-2045(08)70285-7 CrossRefPubMedPubMedCentralGoogle Scholar
- Kasukabe T, Honma Y, Okabe-Kado J, Higuchi Y, Kato N, Kumakura S (2016) Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells. Oncol Rep 36:968–976. https://doi.org/10.3892/or.2016.4867 CrossRefPubMedGoogle Scholar
- Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426. https://doi.org/10.1146/annurev-pharmtox-011112-140320 CrossRefPubMedPubMedCentralGoogle Scholar
- Ou W, Mulik RS, Anwar A, McDonald JG, He X, Corbin IR (2017) Low-density lipoprotein docosahexaenoic acid nanoparticles induce ferroptotic cell death in hepatocellular carcinoma. Free Rad Biol Med 112:597–607. https://doi.org/10.1016/j.freeradbiomed.2017.09.002 CrossRefPubMedGoogle Scholar