IkappaB/NF-kappaB mediated cisplatin resistance in HeLa cells after low-dose gamma-irradiation is associated with...

Fractionated gamma-irradiation (15 x 2 Gy in 3 weeks) induces a cellular resistance in HeLa cells against cisplatin exposure but not against irradiation. The mechanisms underlying this cellular resistance are associated with major changes in the TNFR1-dependent transduction pathway. The resistant HeLa/B cells exhibit increased levels of NF-kappaB with temporally independent regulation of the subunits NF-kappaB50 and NF-kappaB65. Blocking IkappaB degradation by the proteasome inhibitor PSI, which abolishes the release of the active NF-kappaB protein, induces cell death much more effectively in the parental than in the resistant HeLa/B cells. The translocation of NF-kappaB does not seem to be affected in a similar manner since masking of the translocation sequence by NF-kappaB SN50 enhances cisplatin toxicity to the same degree in both cell lines and overcomes drug resistance. Changes in upstream signaling are suggested by increased sensitivity of the parental HeLa cells to cisplatin in the presence of neutralizing anti-TNFR1. In HeLa/B cells, reduced expression of the 50 kDa silencer of death domain, SODD, is accompanied by constitutive overexpression of a 40-42 kDa SODD-like protein. A possible involvement of SODD in cisplatin resistance is discussed, which may shift the balance between life and death in the TNF receptor pathway to increased NF-kappaB activation.