Tapia Maria A, González-Navarrete Irene, Dalmases Alba, Bosch Marta, Rodriguez-Fanjul Vanesa, Rolfe Mark, Ross Jeffrey S, Mezquita Jovita, Mezquita Cristobal, Bachs Oriol, Gascón Pere, Rojo Federico, Perona Rosario, Rovira Ana, Albanell Joan
Laboratory of Experimental Oncology, Medical Oncology Department, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic i Provincial de Barcelona, Barcelona, Spain.
Cell Cycle. 2007 Sep 15;6(18):2284-92. doi: 10.4161/cc.6.18.4721. Epub 2007 Jul 10.
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.
核因子κB（NFκB）家族由五个亚基（p65/RelA、c-Rel、RelB、p105-p50/NFκB(1)、p100-p52/NFκB(2)）组成，调控许多参与细胞周期、凋亡及其他关键细胞过程的基因的表达。在经典途径中，NFκB的激活依赖于由三个亚基（IKKα、IKKβ和IKKγ/NEMO）组成的IKK复合物的活性。存在一条不依赖IKKβ或IKKγ/NEMO的替代性NFκB激活途径，其中RelB是主要参与者。我们在一组人乳腺癌细胞中发现，IKK/NFκB系统在乳腺癌细胞中通常过度表达，且不同细胞系中各个成员的表达水平存在异质性。阿霉素是用于乳腺癌患者的一种抗癌药物，它激活了NFκB，并且在主要表达经典IKK/NFκB成员的细胞中似乎效果较差。两种NFκB抑制剂，硼替佐米和NEMO结合域抑制肽，可阻止阿霉素诱导的NFκB激活，并增强阿霉素对BT-474细胞的抗肿瘤作用。在HeLa细胞中通过小干扰RNA（siRNA）瞬时下调经典途径成员（p65、p52、c-Rel和IKKγ/NEMO）可增加阿霉素的细胞毒性。相反，沉默替代性途径的关键亚基RelB对阿霉素的细胞毒性没有明显影响。总之，抑制NFκB可使细胞对阿霉素敏感，这直接表明p65、p52、c-Rel和IKKγ/NEMO亚基参与化疗耐药，但RelB不参与。这些发现提示，选择性抑制经典NFκB途径足以增强阿霉素的抗肿瘤作用。
