TAK1 Is a Novel Target in Hepatocellular Carcinoma and Contributes to Sorafenib Resistance
Shunjie Xia1, Lin Ji1, Liye Tao1
1Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China; Zhejiang University Cancer Center, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
Background & Aims:
Identifying novel and actionable targets in hepatocellular carcinoma (HCC) remains an unmet medical need. TAK1 was originally identified as a transforming growth factor-β-activated kinase and was further proved to phosphorylate and activate numerous downstream targets and promote cancer progression. However, the role of TAK1 in developed HCC progression and targeted therapy resistance is poorly understood.
Methods:
The expression of TAK1 or MTDH in HCC cell lines, tumor tissues, and sorafenib-resistant models was analyzed by in silico analysis, quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. In vivo and in vitro experiments were introduced to examine the function of TAK1 or MTDH in HCC and sorafenib resistance using small interfering RNA and pharmacologic inhibitors in combination with or without sorafenib. Co-immunoprecipitation and RNA immunoprecipitation were carried out to determine the binding between TAK1 and FBXW2 or between MTDH and FBXW2 mRNA. Protein half-life and in vitro ubiquitination experiment was performed to validate whether FBXW2 regulates TAK1 degradation.
Results:
Our findings unraveled the clinical significance of TAK1 in promoting HCC and sorafenib resistance. We identified a novel E3 ubiquitin ligase, FBXW2, targeting TAK1 for K48-linked polyubiquitylation and subsequent degradation. We also found that MTDH contributes to TAK1 up-regulation in HCC and sorafenib resistance through binding to FBXW2 mRNA and accelerates its degradation. Moreover, combination of TAK1 inhibitor and sorafenib suppressed the growth of sorafenib-resistant HCCLM3 xenograft in mouse models.
Conclusions:
These results revealed novel mechanism underlying TAK1 protein degradation and highlighted the therapeutic value of targeting TAK1 in suppressing HCC and overcoming sorafenib resistance.
Insights
This study reveals how FBXW2 degrades TAK1, a key driver in hepatocellular carcinoma (HCC) and sorafenib resistance. Targeting TAK1 offers a new strategy to treat resistant HCC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) requires novel therapeutic targets, particularly for overcoming treatment resistance.
- Transforming growth factor-β-activated kinase 1 (TAK1) promotes cancer progression, but its role in advanced HCC and therapy resistance is unclear.
Purpose of the Study:
- To investigate the role of TAK1 in HCC progression and sorafenib resistance.
- To identify mechanisms regulating TAK1 stability and its potential as a therapeutic target.
Main Methods:
- Analyzed TAK1 and MTDH expression in HCC cell lines and tissues using qPCR, Western blotting, and IHC.
- Conducted in vitro and in vivo experiments with siRNA and inhibitors to assess TAK1/MTDH function in HCC and sorafenib resistance.
- Utilized co-immunoprecipitation and RNA immunoprecipitation to determine binding interactions between TAK1, MTDH, and FBXW2.
- Performed protein half-life and ubiquitination assays to validate FBXW2-mediated TAK1 degradation.
Main Results:
- Identified FBXW2 as a novel E3 ubiquitin ligase that targets TAK1 for degradation via K48-linked polyubiquitylation.
- Demonstrated that MTDH promotes TAK1 upregulation in HCC and sorafenib resistance by accelerating FBXW2 mRNA degradation.
- Showed that combining a TAK1 inhibitor with sorafenib suppressed tumor growth in a sorafenib-resistant HCC xenograft model.
Conclusions:
- Unraveled a novel mechanism of TAK1 protein degradation regulated by FBXW2.
- Highlighted MTDH's role in promoting HCC and sorafenib resistance by destabilizing FBXW2.
- Established the therapeutic potential of targeting TAK1 to overcome sorafenib resistance in HCC.
More Related Videos
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:56Treatment Resistant Cancers
02:23Abnormal Proliferation
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...