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Increased expression of T-plastin gene in cisplatin-resistant human cancer cells: identification by mRNA differential
1Department of Biochemistry, Kyushu University School of Medicine, Fukuoka, Japan.
Abstract:
The cellular resistance to the potent anticancer agent cis-diamminedichloroplatinum(II) (cisplatin) is thought to be mediated by multiple mechanisms. The technique of differential display of mRNAs was applied to various cisplatin-resistant cell lines and the corresponding parental sensitive human bladder, prostatic, and head and neck cancer cells in order to identify genes that underlie cisplatin resistance. Twenty-four clones were confirmed by Northern blot analysis to be expressed differentially between resistant and the corresponding sensitive cells. Partial DNA sequences of the eight clones that showed a threefold or greater increase in expression in either the resistant cells (seven clones) or sensitive cells (one clone) revealed that two were derived from the T-plastin gene and one from the tissue factor gene. The abundance of T-plastin mRNA in cisplatin-resistant T24/DDP10 cell was approximately 12 times that in the parental T24 cells. Transfection of T24/DDP10 cells with a vector encoding full-length T-plastin antisense RNA demonstrated that reduced T-plastin expression was associated with increased sensitivity to cisplatin. These results are consistent with the hypothesis that several mechanisms participate cooperatively in the acquisition of cisplatin resistance in human cancer.
Insights
Cellular resistance to cisplatin, a potent anticancer drug, involves multiple mechanisms. This study identified T-plastin as a key gene contributing to cisplatin resistance in human cancers.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Cisplatin (cis-diamminedichloroplatinum(II)) is a widely used anticancer agent.
- Cellular resistance to cisplatin is a significant challenge in cancer treatment, mediated by various mechanisms.
- Understanding the genetic basis of cisplatin resistance is crucial for developing more effective therapies.
Purpose of the Study:
- To identify genes involved in cellular resistance to cisplatin in human cancers.
- To investigate the role of differentially expressed genes in mediating cisplatin resistance.
- To explore potential therapeutic strategies by targeting identified resistance genes.
Main Methods:
- Differential display of messenger RNAs (mRNAs) was employed to compare gene expression profiles.
- Northern blot analysis was used to validate differential gene expression.
- Gene sequencing and transfection studies were performed to confirm gene function.
Main Results:
- Twenty-four differentially expressed clones were identified between cisplatin-resistant and sensitive cancer cell lines.
- The T-plastin gene showed a significant increase in expression in resistant cells.
- Reduced T-plastin expression via antisense RNA transfection increased sensitivity to cisplatin, suggesting its role in resistance.
Conclusions:
- Multiple mechanisms cooperatively contribute to the acquisition of cisplatin resistance in human cancers.
- T-plastin is identified as a key gene involved in mediating cisplatin resistance.
- Targeting T-plastin expression may represent a potential strategy to overcome cisplatin resistance in cancer treatment.