AURKA upregulation plays a role in fibroblast-reduced gefitinib sensitivity in the NSCLC cell line HCC827

Chen,Jia; Lu,Huiqi; Zhou,Wang; Yin,Huabin; Zhu,Lishuang; Liu,Chang; Zhang,Pengfei; Hu,Huimin; Yang,Yili; Han,Huanxing

doi:10.3892/or.2015.3764

AURKA upregulation plays a role in fibroblast-reduced gefitinib sensitivity in the NSCLC cell line HCC827

Authors:
- Jia Chen
- Huiqi Lu
- Wang Zhou
- Huabin Yin
- Lishuang Zhu
- Chang Liu
- Pengfei Zhang
- Huimin Hu
- Yili Yang
- Huanxing Han
View Affiliations

Affiliations: Translational Medicine Center, Changzheng Hospital, Affiliated to The Second Military Medical University, Shanghai, P.R. China, Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, P.R. China, Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, MD, USA
Published online on: January 29, 2015 https://doi.org/10.3892/or.2015.3764
Pages: 1860-1866

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) have been used to treat non-small cell lung carcinoma (NSCLC) patients that have EGFR-activating mutations. EGFR-TKI monotherapy in most NSCLC patients with EGFR mutations who initially respond to EGFR-TKIs results in the development of acquired resistance. We investigated the role of fibroblasts in stromal cell-mediated resistance to gefitinib-induced apoptosis in EGFR-mutant NSCLC cells. While gefitinib induced apoptosis in EGFR-mutant NSCLC cells, apoptosis induction was diminished under stromal co-culture conditions. Protection appeared to be mediated in part by Aurora-A kinase (AURKA) upregulation. The protective effect of stromal cells was significantly reduced by pre-exposure to AURKA-shRNA. We suggest that combinations of AURKA antagonists and EGFR inhibitors may be effective in clinical trials targeting mutant EGFR NSCLCs.

View Figures

View References

1	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar
2	Xue C, Hu Z, Jiang W, et al: National survey of the medical treatment status for non-small cell lung cancer (NSCLC) in China. Lung Cancer. 77:371–375. 2012. View Article : Google Scholar : PubMed/NCBI
3	Yarden Y: The EGFR family and its ligands in human cancer. Signaling mechanisms and therapeutic opportunities. Eur J Cancer. 37:S3–S8. 2001. View Article : Google Scholar
4	Schlessinger J: Cell signaling by receptor tyrosine kinases. Cell. 103:211–225. 2000. View Article : Google Scholar : PubMed/NCBI
5	Zhu H, Cao X, Ali-Osman F, Keir S and Lo HW: EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity. Cancer Lett. 294:101–110. 2010. View Article : Google Scholar : PubMed/NCBI
6	Leu CM, Chang C and Hu C: Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway. Oncogene. 19:1665–1675. 2000. View Article : Google Scholar : PubMed/NCBI
7	Huang SH, Li Y, Chen HG, Rong J and Ye S: Activation of proteinase-activated receptor 2 prevents apoptosis of lung cancer cells. Cancer Invest. 31:578–581. 2013. View Article : Google Scholar : PubMed/NCBI
8	Wang Q and Greene MI: EGFR enhances survivin expression through the phosphoinositide3 (PI-3) kinase signaling pathway. Exp Mol Pathol. 79:100–107. 2005. View Article : Google Scholar : PubMed/NCBI
9	Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 350:2129–2139. 2004. View Article : Google Scholar : PubMed/NCBI
10	Paez JG, Jänne PA, Lee JC, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI
11	Woodburn JR: The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther. 82:241–250. 1999. View Article : Google Scholar : PubMed/NCBI
12	Wakeling AE, Guy SP, Woodburn JR, et al: ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res. 62:5749–5754. 2002.PubMed/NCBI
13	Kobayashi S, Boggon TJ, Dayaram T, et al: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 352:786–792. 2005. View Article : Google Scholar : PubMed/NCBI
14	Balak MN, Gong Y, Riely GJ, et al: Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res. 12:6494–6501. 2006. View Article : Google Scholar : PubMed/NCBI
15	Bean J, Brennan C, Shih JY, et al: MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA. 104:20932–20937. 2007. View Article : Google Scholar : PubMed/NCBI
16	Engelman JA, Zejnullahu K, Mitsudomi T, et al: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 316:1039–1043. 2007. View Article : Google Scholar : PubMed/NCBI
17	Baguley BC: Multiple drug resistance mechanisms in cancer. Mol Biotechnol. 46:308–316. 2010. View Article : Google Scholar : PubMed/NCBI
18	Liotta LA and Kohn EC: The microenvironment of the tumor-host interface. Nature. 411:375–379. 2001. View Article : Google Scholar : PubMed/NCBI
19	Witz IP: Tumor-microenvironment interactions: dangerous liaisons. Adv Cancer Res. 100:203–229. 2008. View Article : Google Scholar : PubMed/NCBI
20	Gottesman MM: Mechanisms of cancer drug resistance. Annu Rev Med. 53:615–627. 2002. View Article : Google Scholar : PubMed/NCBI
21	Cukierman E and Bassi DE: The mesenchymal tumor microenvironment: a drug-resistant niche. Cell Adh Migr. 6:285–296. 2012. View Article : Google Scholar : PubMed/NCBI
22	Flach EH, Rebecca VW, Herlyn M, Smalley KS and Anderson AR: Fibroblasts contribute to melanoma tumor growth and drug resistance. Mol Pharm. 8:2039–2049. 2011. View Article : Google Scholar : PubMed/NCBI
23	Ostman A and Augsten M: Cancer-associated fibroblasts and tumor growth - bystanders turning into key players. Curr Opin Genet Dev. 19:67–73. 2009. View Article : Google Scholar : PubMed/NCBI
24	Johansson AC, Ansell A, Jerhammar F, et al: Cancer-associated fibroblasts induce matrix metalloproteinase-mediated cetuximab resistance in head and neck squamous cell carcinoma cells. Mol Cancer Res. 10:1158–1168. 2012. View Article : Google Scholar : PubMed/NCBI
25	Jansen R, Greenbaum D and Gerstein M: Relating whole-genome expression data with protein-protein interactions. Genome Res. 12:37–46. 2002. View Article : Google Scholar : PubMed/NCBI
26	Sehdev V, Katsha A, Arras J, et al: HDM2 regulation by AURKA promotes cell survival in gastric cancer. Clin Cancer Res. 20:76–86. 2014. View Article : Google Scholar :
27	Zimmer S, Kahl P, Buhl TM, et al: Epidermal growth factor receptor mutations in non-small cell lung cancer influence downstream Akt, MAPK and Stat3 signaling. J Cancer Res Clin Oncol. 135:723–730. 2009. View Article : Google Scholar
28	Ostman A and Augsten M: Cancer-associated fibroblasts and tumor growth - bystanders turning into key players. Curr Opin Genet Dev. 19:67–73. 2009. View Article : Google Scholar : PubMed/NCBI
29	Bhowmick NA, Neilson EG and Moses HL: Stromal fibroblasts in cancer initiation and progression. Nature. 432:332–337. 2004. View Article : Google Scholar : PubMed/NCBI
30	Donev IS, Wang W, Yamada T, et al: Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer. Clin Cancer Res. 17:2260–2269. 2011. View Article : Google Scholar : PubMed/NCBI
31	Giet R and Prigent C: Aurora/Ipl1p-related kinases, a new oncogenic family of mitotic serine-threonine kinases. J Cell Sci. 112:3591–3610. 1999.PubMed/NCBI
32	Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PN and Gandara DR: Aurora kinases as anticancer drug targets. Clin Cancer Res. 14:1639–1648. 2008. View Article : Google Scholar : PubMed/NCBI
33	Nishimura Y, Endo T, Kano K and Naito K: Porcine Aurora A accelerates Cyclin B and Mos synthesis and promotes meiotic resumption of porcine oocytes. Anim Reprod Sci. 113:114–124. 2009. View Article : Google Scholar
34	Anand S, Penrhyn-Lowe S and Venkitaraman AR: Aurora-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to taxol. Cancer Cell. 3:51–62. 2003. View Article : Google Scholar : PubMed/NCBI
35	Katayama H, Sasai K, Kawai H, et al: Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet. 36:55–62. 2004. View Article : Google Scholar : PubMed/NCBI