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Physical interaction between human ribonucleotide reductase large subunit and thioredoxin increases colorectal cancer
Meng Lou1, Qian Liu1, Guoping Ren2
1From the Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
The Journal of Biological Chemistry
|April 16, 2017
Summary
Human thioredoxin1 (hTrx1) and Ribonucleotide reductase large subunit (RRM1) are upregulated in colorectal cancer (CRC), promoting DNA synthesis and malignancy. Their interaction suggests a new therapeutic target for CRC treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Ribonucleotide reductase (RR) is crucial for DNA synthesis, with its activity regulated by redox proteins like thioredoxin (Trx) and glutaredoxin (Grx).
- Dysregulation of DNA synthesis is a hallmark of cancer, making enzymes like RR potential targets for anticancer therapies.
Purpose of the Study:
- To investigate the role of human thioredoxin1 (hTrx1) and human glutaredoxin1 (hGrx1) in colorectal cancer (CRC) progression.
- To explore the interaction between hTrx1 and the RR large subunit (RRM1) as a potential therapeutic target in CRC.
Main Methods:
- Immunohistochemical analysis of clinical CRC specimens to assess hTrx1 and RRM1 expression.
- In vitro studies to evaluate the effect of hTrx1 on RR activity, DNA synthesis, and cell behavior.
- In vivo studies using xenograft mice to assess the synergistic effect of inhibiting hTrx1 and RRM1.
Main Results:
- hTrx1, but not hGrx1, was upregulated along with RRM1 in CRC tissues, correlating with malignancy stage.
- Ectopic expression of hTrx1 enhanced RR activity, DNA synthesis, cell proliferation, and migration.
- Inhibition of hTrx1 and RRM1 showed synergistic anticancer effects in CRC cells and xenograft models.
- hTrx1 directly interacted with RRM1, with specific cysteine residues in both proteins being essential for this interaction and RRM1 regeneration.
Conclusions:
- The RRM1-hTrx1 interaction promotes RR activity, DNA synthesis, and CRC malignancy.
- Targeting the RRM1-hTrx1 interaction presents a novel therapeutic strategy for colorectal cancer treatment.