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[Cell signaling and CDDP resistance]
1Dept. of Internal Medicine, Kyushu University, Faculty of Medicine.
Abstract:
Although evidence exists that intracellular signaling through oncogene products may play a role in the resistance of anticancer drugs, the underlying mechanism remains to be clarified. Using a HAG-1 cell line as a human epithelial model, we have studied the alteration of drug sensitivity and determined the mechanism of resistance induced in HAG-1 cells transfected with various oncogenes, which are highly expressed and activated in human cancers. Non-tumorigenic HAG-1 cells acquired fully neoplastic phenotype and resistance to Cisplatin (CDDP) by transfection with v-src but not by activated ras oncogene. The src-transfected cells showed a significant decrease in the formation of CDDP-induced DNA interstrand cross-links with rapid removal of these lesions. Upon treatment with src kinase inhibitors, the level of CDDP resistance and the rate of removal were both reduced in src-transformed cells. These results suggest the ability of v-src oncogene product but not ras to induce CDDP resistance by modulating the certain DNA repair pathway. Thus, intracellular signaling may be the appropriate target for strategies to reverse the drug resistance. In this review, we discuss the role of oncogenes important for signal transduction such as ras and those with protein tyrosine kinase activity in the drug resistance.
Insights
The v-src oncogene confers resistance to Cisplatin (CDDP) chemotherapy by altering DNA repair pathways. Targeting intracellular signaling pathways may reverse this drug resistance in cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Context:
- Intracellular signaling pathways involving oncogenes are implicated in anticancer drug resistance.
- The precise mechanisms underlying oncogene-induced drug resistance require further elucidation.
- Human epithelial models are crucial for studying cancer development and drug response.
Purpose:
- To investigate the role of specific oncogenes, v-src and ras, in mediating resistance to Cisplatin (CDDP).
- To determine the molecular mechanisms by which oncogenes influence drug sensitivity and DNA repair.
- To explore the potential of targeting intracellular signaling for overcoming anticancer drug resistance.
Summary:
- Transfection of HAG-1 cells with the v-src oncogene, but not the activated ras oncogene, induced a neoplastic phenotype and resistance to Cisplatin (CDDP).
- Src-transfected cells exhibited reduced formation of CDDP-induced DNA interstrand cross-links and accelerated DNA repair.
- Inhibition of src kinase activity diminished CDDP resistance and DNA repair rates in src-transformed cells, suggesting v-src modulates DNA repair pathways.
Impact:
- These findings highlight the v-src oncogene's role in conferring Cisplatin resistance through modulation of DNA repair mechanisms.
- The study suggests that intracellular signaling pathways, particularly those involving protein tyrosine kinases like v-src, are viable targets for reversing anticancer drug resistance.
- Understanding oncogene-driven resistance mechanisms can inform the development of novel therapeutic strategies to enhance chemotherapy efficacy.