Effects of the multidrug transporter P-glycoprotein on cellular responses to ionizing radiation.
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.
Ruth
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AC
Department of Molecular Genetics, University of Illinois at Chicago, 60607, USA.
Roninson
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IB
D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D016922:Cellular Senescence / Q000187:drug effects* / Q000528:radiation effects*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects* / Q000528:radiation effects*; D011839:Radiation, Ionizing
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1