title: Inhibition of the canonical IKK/NF kappa B pathway sensitizes human cancer cells to doxorubicin.
abstract: The NF kappa B family is composed by five subunits (p65/RelA, c-Rel, RelB, p105-p50/NF kappa B(1), p100-p52/NF kappa B(2)) and controls the expression of many genes that participate in cell cycle, apoptosis, and other key cellular processes. In a canonical pathway, NF kappa B activation depends on the IKK complex activity, which is formed by three subunits (IKKalpha and IKKbeta and IKKgamma/NEMO). There is an alternative NF kappa B 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/NF kappa B 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 NF kappa B and appeared to be less effective in cells expressing predominantly members of the canonical IKK/NF kappa B. Two NF kappa B inhibitors, bortezomib and NEMO-Binding Domain Inhibitory Peptide, prevented doxorubicin-induced NF kappa B 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, NF kappa B 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 NF kappa B pathway is sufficient to improve doxorubicin antitumor effects.
authors: Laboratory of Experimental Oncology, Medical Oncology Department, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic i Provincial de Barcelona, Barcelona, Spain.
authors: Maria A
authors: MA
authors: Tapia
authors: Irene
authors: I
authors: González-Navarrete
authors: Alba
authors: A
authors: Dalmases
authors: Marta
authors: M
authors: Bosch
authors: Vanesa
authors: V
authors: Rodriguez-Fanjul
authors: Mark
authors: M
authors: Rolfe
authors: Jeffrey S
authors: JS
authors: Ross
authors: Jovita
authors: J
authors: Mezquita
authors: Cristobal
authors: C
authors: Mezquita
authors: Oriol
authors: O
authors: Bachs
authors: Pere
authors: P
authors: Gascón
authors: Federico
authors: F
authors: Rojo
authors: Rosario
authors: R
authors: Perona
authors: Ana
authors: A
authors: Rovira
authors: Joan
authors: J
authors: Albanell
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D004317:Doxorubicin; D051550:I-kappa B Kinase