ASPH dysregulates cell death and induces chemoresistance in hepatocellular carcinoma
Jingtao Li1, Guocai Zhong1, Fengli Hu2
1Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, PR China.
Abstract:
Hepatocellular carcinoma (HCC) is resistant to multiple conventional drugs including sorafenib, leading to poor prognosis. Inducing cell death has been inextricably pursued in therapeutics, although targeted therapy and immunotherapy have made very limited progress. ASPH (Aspartate β-hydroxylase) can be breakthrough in meeting this unmet clinical need. In HCC, high expression of ASPH enhanced proliferation, migration and invasion. High levels of ASPH predicted worse clinical outcomes of sorafenib-treated HCC patients. Mechanistically, ASPH upregulated SQSTM1/P62 and SLC7A11-GPX4 axis, thereby promoting tumor cell autophagy but blocking ferroptosis. Sorafenib-induced enhancement of autophagy was attenuated by knockout (KO) of ASPH, resulting in sensitization of tumor cells to sorafenib. By silencing ASPH combined with sorafenib, senescence, apoptosis and ferroptosis were mediated, whereas proliferation, migration, invasion, tube formation and stemness were inhibited. As validated by in vivo murine models of HCC, ASPH promoted tumor growth, distant metastasis, and resistance to sorafenib. By contrast, KO ASPH combined with sorafenib effectively inhibited tumor development and progression, including intrahepatic, pulmonary, and splenic metastases. Targeting ASPH generated antitumor efficacy will pave the way for HCC therapy.
Insights
Aspartate β-hydroxylase (ASPH) drives hepatocellular carcinoma (HCC) growth and sorafenib resistance by blocking ferroptosis. Silencing ASPH sensitizes HCC cells to sorafenib, promoting cell death and inhibiting metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Hepatocellular carcinoma (HCC) exhibits resistance to conventional therapies like sorafenib, necessitating novel therapeutic strategies.
- Targeted therapy and immunotherapy have shown limited efficacy in improving HCC patient outcomes.
- Inducing cancer cell death remains a critical goal in HCC treatment.
Purpose of the Study:
- To investigate the role of Aspartate β-hydroxylase (ASPH) in HCC progression and sorafenib resistance.
- To explore the therapeutic potential of targeting ASPH in combination with sorafenib for HCC treatment.
Main Methods:
- Assessed ASPH expression in HCC and its correlation with clinical outcomes.
- Utilized gene knockout (KO) and silencing techniques to manipulate ASPH levels in HCC cells.
- Investigated the molecular mechanisms involving the SQSTM1/P62 and SLC7A11-GPX4 axis.
- Validated findings using in vivo murine models of HCC.
Main Results:
- High ASPH expression in HCC promotes proliferation, migration, invasion, and predicts poor outcomes in sorafenib-treated patients.
- ASPH upregulates autophagy via SQSTM1/P62 while inhibiting ferroptosis through the SLC7A11-GPX4 axis.
- ASPH knockout (KO) sensitizes HCC cells to sorafenib by attenuating autophagy and promoting apoptosis and ferroptosis.
- Combined ASPH silencing and sorafenib treatment inhibited tumor growth, metastasis, and stemness in vivo.
Conclusions:
- ASPH plays a critical role in promoting HCC growth, metastasis, and resistance to sorafenib.
- Targeting ASPH in combination with sorafenib demonstrates significant antitumor efficacy.
- ASPH inhibition represents a promising therapeutic strategy for overcoming sorafenib resistance in HCC.
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