Inhibition of the Canonical IKK/NFkappaB Pathway Sensitizes Human Cancer Cells to Doxorubicin.
[Today's bortezomib abstract: Why working with doxorubicin might make sense.]
Cell Cycle. 2007 Jul 10;6(18)
Tapia MA, González-Navarrete I, Dalmases A, Bosch M, Rodriguez-Fanjul V, Rolfe M, Ross JS, Mezquita J, Mezquita C, Bachs O, Gascón P, Rojo F, Perona R, Rovira A, Albanell J.
Laboratory of Experimental Oncology, Medical Oncology Department, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic i Provincial de Barcelona, Barcelona, Spain.
The NFkappaB family is composed by five subunits (p65/RelA, c-Rel, RelB, p105-p50/NFkappaB1, p100-p52/NFkappaB(2)) and controls the expression of many genes that participate in cell cycle, apoptosis, and other key cellular processes. In a canonical pathway, NFkappaB activation depends on the IKK complex activity, which is formed by three subunits (IKKalpha and IKKbeta and IKKgamma/NEMO). There is an alternative NFkappaB activation pathway that does not require IKKbeta or IKKgamma/NEMO, in which RelB is a major player. We report in a panel of human breast cancer cells that the IKK/NFkappaB system is generally overexpressed in breast cancer cells and there is heterogeneity in expression levels of individual members between different cell lines. Doxorubicin, an anticancer agent used in patients with breast cancer, activated NFkappaB and appeared to be less effective in cells expressing predominantly members of the canonical IKK/NFkappaB. Two NFkappaB inhibitors, bortezomib and NEMO-Binding Domain Inhibitory Peptide, prevented doxorubicin-induced NFkappaB activation and increased doxorubicin antitumor effects in BT-474 cells. Transient down-regulation of members of the canonical pathway (p65, p52, c-Rel and IKKgamma/NEMO) by siRNA in HeLa cells increased doxorubicin cytotoxicity. In contrast, silencing of RelB, a key subunit of the alternative pathway, had no evident effects on doxorubicin cytotoxicity. To conclude, NFkappaB inhibition sensitized cells to doxorubicin, implying directly p65, p52, c-Rel and IKKgamma/NEMO subunits in chemoresistance, but not RelB. These findings suggest that selective inhibition of the canonical NFkappaB pathway is sufficient to improve doxorubicin antitumor effects. |
