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Effects of the multidrug transporter P-glycoprotein on cellular responses to ionizing radiation
1Department of Molecular Genetics, University of Illinois at Chicago, 60607, USA.
Abstract:
Ionizing radiation induces apoptosis, mitotic catastrophe, and senescence-like terminal proliferation arrest in tumor cells. We investigated the effect of the MDR1 P-glycoprotein (Pgp), recently shown to inhibit caspase-mediated apoptosis, on cellular responses to radiation. Pgp strongly inhibited radiation-induced apoptosis in a HeLa-derived cell line with inducible MDR1 expression and in NIH 3T3 cells transduced with a MDR1-expressing retroviral vector. The inhibition of apoptosis by Pgp was associated, however, with increases in radiation-induced mitotic catastrophe and senescence and produced only a marginal change in the survival of irradiated cells. Pgp had no effect on radiation responses in apoptosis-resistant HT1080 cells. These results indicate that Pgp inhibits radiation-induced apoptosis, but this effect of Pgp provides no substantial increase in radiation resistance of the tested cell lines because apoptosis-resistant cells die from mitotic catastrophe or undergo senescence-like terminal proliferation arrest.
Insights
P-glycoprotein (Pgp) inhibits radiation-induced apoptosis in tumor cells. However, this inhibition does not significantly increase cell survival, as cells undergo other death pathways like mitotic catastrophe or senescence.
Area of Science:
- Oncology
- Cell Biology
- Radiation Biology
Background:
- Ionizing radiation triggers apoptosis, mitotic catastrophe, and senescence in tumor cells.
- P-glycoprotein (Pgp) is known to inhibit caspase-mediated apoptosis.
Purpose of the Study:
- To investigate the impact of P-glycoprotein (Pgp) on cellular responses to ionizing radiation.
- To determine if Pgp-mediated inhibition of apoptosis affects overall tumor cell survival after radiation exposure.
Main Methods:
- Utilized a HeLa-derived cell line with inducible MDR1 expression.
- Employed NIH 3T3 cells transduced with a MDR1-expressing retroviral vector.
- Assessed cellular responses including apoptosis, mitotic catastrophe, and senescence following radiation treatment in the presence and absence of Pgp.
Main Results:
- P-glycoprotein (Pgp) significantly inhibited radiation-induced apoptosis in tested cell lines.
- This inhibition of apoptosis was accompanied by increased rates of mitotic catastrophe and senescence.
- Pgp had a marginal effect on the overall survival of irradiated cells and no effect on apoptosis-resistant cells.
Conclusions:
- P-glycoprotein (Pgp) effectively inhibits radiation-induced apoptosis in tumor cells.
- The inhibition of apoptosis by Pgp does not lead to substantial increases in radiation resistance due to compensatory cell death mechanisms.
- Tumor cells lacking apoptosis susceptibility may succumb to mitotic catastrophe or senescence-like arrest following radiation exposure.