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Drug resistance results in alterations in expression of immune recognition molecules and failure to express Fas
A Bhushan1, J L Kupperman, J E Stone
1Department of Pharmacology, Vermont Cancer Center, University of Vermont College of Medicine, Burlington 05405, USA.
Abstract:
It is demonstrated that methotrexate/cisplatin-sensitive L1210 cells express low levels of major histocompatibility complex (MHC) class II relative to the high levels expressed on methotrexate (MTX)/cisplatin-resistant L1210/DDP cells. L1210 cells express cell-surface Fas, while the L1210/DDP cells express no cell-surface Fas. Expression of costimulatory molecules B7-1/B7-2 and Fas is increased on L1210 cells, but not L1210/DDP, in the presence of methotrexate or trimetrexate (TMTX). Therefore, a component of the mechanism of action of some anti-cancer agents may be to facilitate immune recognition and T cell-directed, Fas-induced cell death. Loss of cell-surface Fas expression and failure of Fas (CD95)-dependent apoptotic death has been observed when cells develop drug resistance. The defect in apoptosis can be overcome by anti-cancer agents or experimental manipulation that induce Fas expression on the drug-resistant cells.
Insights
Drug-resistant cancer cells may evade immune detection by downregulating Fas. However, certain anti-cancer drugs can restore Fas expression, enabling immune cells to induce cancer cell death.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Drug resistance in cancer is a significant clinical challenge.
- Major Histocompatibility Complex (MHC) class II and Fas expression are critical for immune recognition and apoptosis.
- Methotrexate (MTX)/cisplatin-resistant L1210/DDP cells exhibit distinct immune molecule profiles compared to sensitive L1210 cells.
Purpose of the Study:
- To investigate the role of MHC class II and Fas expression in chemoresistance.
- To explore the impact of anti-cancer agents on immune recognition and apoptosis in drug-resistant cancer cells.
- To elucidate mechanisms by which cancer cells develop resistance to apoptosis.
Main Methods:
- Comparative analysis of MHC class II and Fas expression on sensitive (L1210) and resistant (L1210/DDP) cell lines.
- Assessment of costimulatory molecule (B7-1/B7-2) and Fas expression following treatment with methotrexate or trimetrexate (TMTX).
- Evaluation of Fas-induced apoptosis in drug-resistant cells.
Main Results:
- Methotrexate/cisplatin-sensitive L1210 cells express low MHC class II, while resistant L1210/DDP cells express high levels.
- L1210 cells express cell-surface Fas, whereas L1210/DDP cells lack it.
- Methotrexate or trimetrexate increased B7-1/B7-2 and Fas expression on L1210 cells, but not L1210/DDP cells.
- Loss of Fas expression is linked to drug resistance and impaired Fas-dependent apoptosis.
- Anti-cancer agents can restore Fas expression and overcome apoptosis defects in resistant cells.
Conclusions:
- Anti-cancer agents may function by enhancing immune recognition and Fas-mediated apoptosis.
- Acquired chemoresistance can involve the downregulation of cell-surface Fas, leading to failed apoptotic death.
- Inducing Fas expression on drug-resistant cells presents a potential therapeutic strategy to restore sensitivity and promote cancer cell death.