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Inhibition of the Canonical IKK/NFκB Pathway Sensitizes Human Cancer Cells to Doxorubicin

Maria A. Tapia, Irene González-Navarrete, Alba Dalmases, Marta Bosch, Vanesa Rodriguez-Fanjul, Mark Rolfe, Jeffrey S. Ross, Jovita Mezquita, Cristobal Mezquita, Oriol Bachs, Pere Gascón, Federico Rojo, Rosario Perona, Ana Rovira and Joan Albanell

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The NFκB family is composed by five subunits (p65/RelA, c-Rel, RelB, p105-p50/NFκB1, p100-p52/NF-κB2) and controls the expression of many genes that participate in cell cycle, apoptosis, and other key cellular processes. In a canonical pathway, NF-κB activation depends on the IKK complex activity, which is formed by three subunits (IKKα and IKKβ and IKKγ/NEMO). There is an alternative NFκB activation pathway that does not require IKKβ or IKKγ/NEMO, in which RelB is a major player. We report in a panel of human breast cancer cells that the IKK/NFκB 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 NFκB and appeared to be less effective in cells expressing predominantly members of the canonical IKK/NFκB. Two NFκB inhibitors, bortezomib and NEMO-Binding Domain Inhibitory Peptide, prevented doxorubicin-induced NFκB activation and increased doxorubicin antitumor effects in BT-474 cells. Transient downregulation of members of the canonical pathway (p65, p52, c-Rel and IKKγ/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, NFκB inhibition sensitized cells to doxorubicin, implying directly p65, p52, c-Rel and IKKγ/NEMO subunits in chemoresistance, but not RelB. These findings suggest that selective inhibition of the canonical NFκB pathway is sufficient to improve doxorubicin antitumor effects.

Authors

Maria A. Tapia

Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS); Barcelona, Spain

Irene González-Navarrete

IMIM-Hospital del Mar; Barcelona, Spain

Alba Dalmases

IMIM-Hospital del Mar; Barcelona, Spain

Marta Bosch

Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS); Barcelona, Spain

Vanesa Rodriguez-Fanjul

Instituto de Investigaciones Biomédicas CSIC-UAM; Madrid, Spain

Mark Rolfe

Millennium Pharmaceuticals, Inc.; Cambridge, Massachusetts

Jeffrey S. Ross

Millennium Pharmaceuticals, Inc.; Cambridge, Massachusetts

Jovita Mezquita

University of Barcelona; Barcelona, Spain

Cristobal Mezquita

University of Barcelona; Barcelona, Spain

Oriol Bachs

University of Barcelona; Barcelona, Spain

Pere Gascón

Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS); Barcelona, Spain

Federico Rojo

IMIM-Hospital del Mar; Barcelona, Spain

Rosario Perona

Instituto de Investigaciones Biomd0069cas CSIC-UAM; Madrid, Spain

Ana Rovira

Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS); Barcelona, Spain

Joan Albanell

Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS); Barcelona, Spain

Purchase article for $19

Subscribe to this journal for $129/year