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Role of tumor necrosis factor alpha-induced protein 1 in paclitaxel resistance
1Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China.
Abstract:
Paclitaxel has been extensively used as an antitumor drug to treat a broad range of epithelial cancers, including breast and cervical cancers. However, the efficacy of this drug is greatly limited by the development of acquired resistance. Identification of the underlying resistance mechanisms may inform the development of new therapies that elicit long-term response of tumors to paclitaxel treatment. Here we report that increased expression of TNFAIP1 (tumor necrosis factor alpha-induced protein 1) confers acquired resistance to paclitaxel. TNFAIP1 is shown to compete with paclitaxel for binding to β-tubulin, thereby preventing paclitaxel-induced tubulin polymerization, cell cycle arrest and ultimate cell death. We also show that expression of TNFAIP1 is regulated by the transcriptional factor Sp1. In a xenograft mouse model, increased expression of TNFAIP1 decreases, whereas knockdown of TNFAIP1 increases tumor response to paclitaxel. Therefore, these results reveal tnfaip1 as a novel paclitaxel-resistance associated gene and suggest that TNFAIP1 may represent a valuable therapeutic target for the treatment of cancer.
Insights
Increased tumor necrosis factor alpha-induced protein 1 (TNFAIP1) expression causes acquired resistance to paclitaxel by interfering with tubulin polymerization. TNFAIP1 represents a potential therapeutic target for overcoming paclitaxel resistance in epithelial cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Paclitaxel is a key chemotherapy agent for epithelial cancers.
- Acquired resistance significantly limits paclitaxel's long-term efficacy.
- Understanding resistance mechanisms is crucial for developing improved cancer therapies.
Purpose of the Study:
- To identify novel genes associated with acquired paclitaxel resistance.
- To elucidate the functional role of TNFAIP1 in paclitaxel resistance.
- To explore TNFAIP1 as a potential therapeutic target.
Main Methods:
- Investigated TNFAIP1 expression in paclitaxel-resistant cancer models.
- Examined the interaction between TNFAIP1 and β-tubulin.
- Assessed the impact of TNFAIP1 modulation on paclitaxel sensitivity in vitro and in vivo.
- Analyzed TNFAIP1 regulation by Sp1.
Main Results:
- Increased TNFAIP1 expression confers acquired resistance to paclitaxel.
- TNFAIP1 competes with paclitaxel for β-tubulin binding, inhibiting polymerization and cell death.
- Sp1 transcriptionally regulates TNFAIP1 expression.
- In vivo studies showed TNFAIP1 overexpression reduces tumor response, while knockdown enhances it.
Conclusions:
- TNFAIP1 is a novel gene conferring paclitaxel resistance.
- TNFAIP1's mechanism involves direct interference with paclitaxel's action on tubulin.
- Targeting TNFAIP1 may restore sensitivity to paclitaxel in resistant cancers.
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