title: Lapatinib inhibits the activation of NF-κB through reducing phosphorylation             of IκB-α in breast cancer cells.
abstract: Lapatinib is highly active against breast cancer with HER2 overexpression             in preclinical and clinical settings. Constitutive activation of NF-κB is linked             to proliferation and apoptosis in breast cancer cells. NF-κB can be activated             by HER2 in breast cancer cells. However, the effect of lapatinib on NF-κB activity             is not completely clear. In this study, we showed that lapatinib potently inhibited             activation of NF-κB in HER2-overexpressing breast cancer cells, including SKBR3             and MDA-MB-453; but not in non-HER2-overexpressing breast cancer cells, MDA-MB-231,             MDA-MB-468 and MDA-MB‑435. In addition, we established a model of acquired resistance             to lapatinib by chronically challenging SKBR3 breast cancer cells with increasing             concentrations of lapatinib. EMSA assays showed that there was decreased NF-κB             activity in the resistant cells. Western blot analysis showed that lapatinib reduced             the phosphorylation of IκB-α in a time- and dose-dependent manner in SKBR3 cells.             Furthermore, the expression level of p-IκB-α protein was markedly decreased in             the resistant cells, compared with the parental SKBR3 cells. Additionally, treatment             with the PI3K inhibitor LY294002 dramatically inhibited activation of NF-κB in             HER2-overexpressing breast cancer cells. Moreover, LY294002 inhibited phosphorylation             of Akt and IκB-α in SKBR3 cells. Our results suggest that lapatinib potently inhibits             the activation of NF-κB in HER2-overexpressing breast cancer cells. Lapatinib             appears to inactivate NF-κB through reducing phosphorylation of IκB-α via blocking             the PI3K/Akt cascade.
authors.affiliation: Breast Oncology Centre, Shandong Tumor Hospital and Institute, Shandong Academy of Medical Sciences, Jinan 250117, PR China. mcd7301@hotmail.com
authors.forename: Chuandong
authors.initials: C
authors.lastname: Ma
authors.forename: Wenshu
authors.initials: W
authors.lastname: Zuo
authors.forename: Xingwu
authors.initials: X
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
authors.forename: Qian
authors.initials: Q
authors.lastname: Guo
authors.forename: Xianrang
authors.initials: X
authors.lastname: Song
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D000077341:Lapatinib; D009025:Morpholines / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D020672:I-kappa B Proteins; D000077341:Lapatinib; D009025:Morpholines; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C000606204:NFKBIA protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C508053:ERBB2 protein, human