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Decreased sensitivity of carcinoembryonic antigen cDNA-transfected cells to adriamycin
H Kawaharata1, Y Hinoda, F Itoh
1First Department of Internal Medicine, Sapporo Medical University, Chuo-ku, Japan.
Abstract:
Carcinoembryonic antigen (CEA) is a heavily glycosylated protein and is expressed at a high frequency in adenocarcinomas, which are known to be one of the cancers most resistant to chemotherapeutic agents. In this study, with the aim to elucidate whether CEA participates in drug resistance or not, we tested the adriamycin (ADR) sensitivity of CEA transfectants of H-ras-transformed NIH 3T3 cells in vitro and in vivo. The ADR sensitivity of CEA transfectants in vitro was evaluated as growth (% of control) when incubated with various concentrations of ADR, and showed that they were higher than those of mock transfectants. The decreased ADR sensitivity of CEA transfectants in vivo was also observed as an increase in tumor size after intraperitoneal administration of ADR into SCID mice. To define the mechanisms for resistance, the accumulation and efflux of ADR in transfectants was examined. The rate of ADR accumulation in CEA transfectants was reduced compared to mock transfectants, caused at least partly by an increased efflux out of the cells. Furthermore, the modification of N-glycan on CEA by deoxymannojirimycin, an N-glycosylation processing inhibitor, partially restored ADR sensitivity of CEA transfectants, suggesting an involvement of sugar chains. Our data suggest that CEA expression may decrease ADR sensitivity of cancer cells.
Insights
Carcinoembryonic antigen (CEA) expression may reduce cancer cells' sensitivity to adriamycin (ADR). Modifying CEA's sugar chains partially restored drug sensitivity, suggesting CEA's role in chemotherapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Carcinoembryonic antigen (CEA) is a protein frequently found in adenocarcinomas.
- Adenocarcinomas are often resistant to chemotherapy.
- The role of CEA in drug resistance is not well understood.
Purpose of the Study:
- To investigate if Carcinoembryonic antigen (CEA) expression contributes to adriamycin (ADR) resistance in cancer cells.
- To elucidate the mechanisms underlying CEA-mediated drug resistance.
Main Methods:
- CEA was transfected into H-ras-transformed NIH 3T3 cells.
- Adriamycin (ADR) sensitivity was assessed in vitro and in vivo.
- Adriamycin (ADR) accumulation and efflux were measured.
- N-glycosylation processing was inhibited using deoxymannojirimycin.
Main Results:
- CEA transfectants exhibited reduced sensitivity to ADR in vitro and in vivo.
- ADR accumulation was lower in CEA transfectants, with increased efflux.
- Inhibiting N-glycosylation partially restored ADR sensitivity.
Conclusions:
- CEA expression appears to decrease the sensitivity of cancer cells to adriamycin (ADR).
- CEA-mediated drug resistance may involve altered drug accumulation and efflux.
- The glycosylation of CEA might play a role in this resistance mechanism.