Lapatinib inhibits the activation of NF-κB through reducing phosphorylation of IκB-α in breast cancer cells

Ma,Chuandong; Zuo,Wenshu; Wang,Xingwu; Wei,Ling; Guo,Qian; Song,Xianrang

doi:10.3892/or.2012.2159

Lapatinib inhibits the activation of NF-κB through reducing phosphorylation of IκB-α in breast cancer cells

Authors:
- Chuandong Ma
- Wenshu Zuo
- Xingwu Wang
- Ling Wei
- Qian Guo
- Xianrang Song
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Affiliations: Breast Oncology Centre, Shandong Tumor Hospital and Institute, Shandong Academy of Medical Sciences, Jinan 250117, P.R. China, Basic Research Centre, Shandong Tumor Hospital and Institute, Shandong Academy of Medical Sciences, Jinan 250117, P.R. China
Published online on: November 29, 2012 https://doi.org/10.3892/or.2012.2159
Pages: 812-818

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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.

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1	Citri A and Yarden Y: EGF-ERBB signaling: towards the systems level. Nat Rev Mol Cell Biol. 7:505–516. 2006. View Article : Google Scholar : PubMed/NCBI
2	Landgraf R: HER2 (ERBB2)-functional diversity from structurally conserved building blocks. Breast Cancer Res. 9:2022007. View Article : Google Scholar : PubMed/NCBI
3	Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 235:177–182. 1987. View Article : Google Scholar : PubMed/NCBI
4	Esteva F, Yu D, Hung M and Hortobagyi G: Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat Rev Clin Oncol. 2:98–107. 2010. View Article : Google Scholar : PubMed/NCBI
5	Rusnak DW, Lackey K, Affleck K, et al: The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther. 1:85–94. 2001.
6	Ma C, Niu X, Luo J, Shao Z and Shen K: Combined effects of lapatinib and bortezomib in human epidermal receptor 2 (HER2)-overexpressing breast cancer cells and activity of bortezomib against lapatinib-resistant breast cancer cells. Cancer Sci. 10:2220–2226. 2010. View Article : Google Scholar
7	Konecny GE, Pegram MD, Venkatesan N, et al: Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 66:1630–1639. 2006. View Article : Google Scholar : PubMed/NCBI
8	Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 355:2733–2743. 2006. View Article : Google Scholar : PubMed/NCBI
9	Johnston S, Pippen J Jr, Pivot X, et al: Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 27:5538–5546. 2009. View Article : Google Scholar
10	Ghosh S, May MJ and Kopp EB: NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 16:225–260. 1998.
11	Hayden MS and Ghosh S: Shared principles in NF-kappaB signaling. Cell. 3:344–362. 2008. View Article : Google Scholar : PubMed/NCBI
12	Zheng C, Yin Q and Wu H: Structural studies of NF-κB signaling. Cell Res. 1:183–195. 2011.
13	Biswas DK, Shi Q, Baily S, et al: NF-κB activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci USA. 101:10137–10142. 2004.
14	Merkhofer E, Cogswell P and Baldwin A: Her2 activates NF-κB and induces invasion through the canonical pathway involving IKKα. Oncogene. 8:1238–1248. 2010.
15	Liu M, Ju X, Willmarth N, et al: Nuclear factor-κB enhances ErbB2-induced mammary tumorigenesis and neoangiogenesis in vivo. Am J Pathol. 5:1910–1920. 2009.
16	Montagut C, Tusquets I, Ferrer B, et al: Activation of nuclear factor-κB is linked to resistance to neoadjuvant chemotherapy in breast cancer patients. Endocr Relat Cancer. 2:607–616. 2006.
17	Manna S, Manna P and Sarkar A: Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells. Cell Death Differ. 1:158–170. 2007. View Article : Google Scholar : PubMed/NCBI
18	deGraffenried L, Chandrasekar B, Friedrichs W, et al: NF-κB inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen. Ann Oncol. 15:885–890. 2004.
19	Papanikolaou V, Iliopoulos D, Dimou I, et al: Survivin regulation by HER2 through NF-κB and c-myc in irradiated breast cancer cells. J Cell Mol Med. 7:1542–1550. 2011.
20	Rivas M, Tkach M, Beguelin W, et al: Transactivation of ErbB-2 induced by tumor necrosis factor α promotes NF-κB activation and breast cancer cell proliferation. Breast Cancer Res Treat. 122:111–124. 2010.
21	Guo G, Wang T, Gao Q, et al: Expression of ErbB2 enhances radiation-induced NF-κB activation. Oncogene. 23:535–545. 2004.PubMed/NCBI
22	LaBonte M, Wilson P, Fazzone W, et al: The dual EGFR/HER2 inhibitor lapatinib synergistically enhances the antitumor activity of the histone deacetylase inhibitor panobinostat in colorectal cancer models. Cancer Res. 10:3635–3648. 2011. View Article : Google Scholar
23	Liu L, Greger J, Shi H, et al: Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res. 69:6871–6878. 2009. View Article : Google Scholar : PubMed/NCBI
24	Aird K, Ghanayem R, Peplinski S, Lyerly H and Devi G: X-Linked inhibitor of apoptosis protein inhibits apoptosis in inflammatory breast cancer cells with acquired resistance to an ErbB1/2 tyrosine kinase inhibitor. Mol Cancer Ther. 5:1432–1442. 2010. View Article : Google Scholar : PubMed/NCBI
25	Huang C, Park C, Hilsenbeck S, et al: β1 Integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res. 4:R842011.
26	Karin M: Nuclear factor-kappaB in cancer development and progression. Nature. 441:431–436. 2006. View Article : Google Scholar : PubMed/NCBI
27	Miyakoshi J and Yagi K: Inhibition of IκB-α phosphorylation at serine and tyrosine acts independently on sensitization to DNA damaging agents in human glioma cells. Br J Cancer. 1:28–33. 2000.
28	Wu H, Li W, Wang T, Shu Y and Liu P: Paeoniflorin suppress NF-κB activation through modulation of IκBα and enhances 5-fluorouracil-induced apoptosis in human gastric carcinoma cells. Biomed Pharmacother. 9:659–666. 2008.
29	Salminen A and Kaarniranta K: Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-κB signaling. Cell Signal. 4:573–577. 2010.PubMed/NCBI
30	Romashkova JA and Makarov SS: NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 401:86–90. 1999.
31	Madrid L, Mayo M, Reuther J and Baldwin A: Akt stimulates the transactivation potential of the RelA/p65subunit of NF-κB through utilization of the IκB kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem. 22:18934–18940. 2001.
32	Dan H, Cooper M, Cogswell P, Duncan J, Ting J and Baldwin A: Akt-dependent regulation of NF-κB is controlled by mTOR and Raptor in association with IKK. Genes Dev. 11:1490–1500. 2008.