Adenomatous polyposis coli determines sensitivity to the EGFR tyrosine kinase inhibitor gefitinib in colorectal cancer cells

Zhang,Yining; Xiao,Qinghuan; Zhang,Huijing; Sun,Xuren; Ge,Huijuan; Liu,Xiaoming; Guan,Lin; Sun,Mingjun

doi:10.3892/or.2014.3041

Adenomatous polyposis coli determines sensitivity to the EGFR tyrosine kinase inhibitor gefitinib in colorectal cancer cells

Authors:
- Yining Zhang
- Qinghuan Xiao
- Huijing Zhang
- Xuren Sun
- Huijuan Ge
- Xiaoming Liu
- Lin Guan
- Mingjun Sun
View Affiliations

Affiliations: Department of Gastrointestinal Endoscopy, The First Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China , Department of Pharmacology, School of Pharmaceutical Science, China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China
Published online on: February 20, 2014 https://doi.org/10.3892/or.2014.3041
Pages: 1811-1817

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 tyrosine kinase inhibitors (EGFR-TKIs) have been used to treat colorectal cancer (CRC). However, resistance to EGFR-TKIs presents a great challenge for the treatment of CRC, and the mechanisms of resistance are poorly understood. The adenomatous polyposis coli (APC) protein has been known to contribute to the carcinogenesis of CRC. However, its role in the sensitivity of CRC cells to gefitinib has not been investigated. Human CRC HCT-116 (wild-type APC) and HT-29 (mutant APC) cells were used to investigate the effect of APC on the sensitivity of CRC cells to gefitinib. The MTT assay was used to measure cell viability after exposure to gefitinib. Cell apoptosis, migration and invasion were determined by flow cytometry, wound healing assay and transwell assay, respectively. Knockdown and overexpression of APC were performed, and activation of the EGFR and its downstream pathway was determined. Gefinitib inhibited viability, promoted apoptosis, and reduced the migration of HCT-116 and HT-29 cells. HT-29 cells exhibited increased sensitivity to gefinitib when compared to HCT-116 cells. Knockdown of APC expression increased the sensitivity of HCT-16 cells to gefitinib, accompanied by downregulation of pEGFR, p-AKT and pERK1/2. In contrast, overexpression of APC decreased the sensitivity of HT-29 cells to gefitinib, accompanied by upregulation of pEGFR, p-AKT and pERK1/2. APC plays an important role in the sensitivity of CRC cells to gefitinib. APC may represent a potential therapeutic target for the treatment of CRC.

View Figures

View References

1	de Castro-Carpeno J, Belda-Iniesta C, Casado Saenz E, Hernandez Agudo E, Feliu Batlle J and Gonzalez Baron M: EGFR and colon cancer: a clinical view. Clin Transl Oncol. 10:6–13. 2008.PubMed/NCBI
2	Fischer von Weikersthal L, Schalhorn A, Stauch M, et al: Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. Eur J Cancer. 47:206–214. 2011.PubMed/NCBI
3	Krasinskas AM: EGFR signaling in colorectal carcinoma. Patholog Res Int. 2011:9329322011.PubMed/NCBI
4	Fodde R and Brabletz T: Wnt/β-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol. 19:150–158. 2007.
5	Wieduwilt MJ and Moasser MM: The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci. 65:1566–1584. 2008. View Article : Google Scholar : PubMed/NCBI
6	Citri A and Yarden Y: EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 7:505–516. 2006. View Article : Google Scholar : PubMed/NCBI
7	Yarom N and Jonker DJ: The role of the epidermal growth factor receptor in the mechanism and treatment of colorectal cancer. Discov Med. 11:95–105. 2011.PubMed/NCBI
8	Albanell J and Gascon P: Small molecules with EGFR-TK inhibitor activity. Curr Drug Targets. 6:259–274. 2005. View Article : Google Scholar : PubMed/NCBI
9	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
10	Ono M and Kuwano M: Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res. 12:7242–7251. 2006. View Article : Google Scholar : PubMed/NCBI
11	Zhou C, Wu YL, Chen G, et al: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12:735–742. 2011. View Article : Google Scholar : PubMed/NCBI
12	Maemondo M, Inoue A, Kobayashi K, et al: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 362:2380–2388. 2010. View Article : Google Scholar : PubMed/NCBI
13	Shi Y, Zhang L, Liu X, et al: Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 14:953–961. 2013. View Article : Google Scholar : PubMed/NCBI
14	Mackenzie MJ, Hirte HW, Glenwood G, et al: A phase II trial of ZD1839 (Iressa) 750 mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer. Invest New Drugs. 23:165–170. 2005. View Article : Google Scholar : PubMed/NCBI
15	Rothenberg ML, LaFleur B, Levy DE, et al: Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol. 23:9265–9274. 2005. View Article : Google Scholar : PubMed/NCBI
16	Trarbach T, Reinacher-Schick A, Hegewisch-Becker S, et al: Gefitinib in combination with capecitabine as second-line therapy in patients with advanced colorectal cancer (aCRC): a phase I/II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Onkologie. 33:89–93. 2010. View Article : Google Scholar
17	Vieitez JM, Valladares M, Pelaez I, et al: A randomized phase II study of raltitrexed and gefitinib versus raltitrexed alone as second line chemotherapy in patients with colorectal cancer. (1839IL/0143). Invest New Drugs. 29:1038–1044. 2011. View Article : Google Scholar : PubMed/NCBI
18	Santoro A, Comandone A, Rimassa L, et al: A phase II randomized multicenter trial of gefitinib plus FOLFIRI and FOLFIRI alone in patients with metastatic colorectal cancer. Ann Oncol. 19:1888–1893. 2008. View Article : Google Scholar : PubMed/NCBI
19	Nathke IS: The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium. Annu Rev Cell Dev Biol. 20:337–366. 2004. View Article : Google Scholar : PubMed/NCBI
20	Fodde R: The APC gene in colorectal cancer. Eur J Cancer. 38:867–871. 2002. View Article : Google Scholar
21	Barker N: The canonical Wnt/β-catenin signalling pathway. Methods Mol Biol. 468:5–15. 2008.
22	Hu T and Li C: Convergence between Wnt-β-catenin and EGFR signaling in cancer. Mol Cancer. 9:2362010.
23	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
24	Paez JG, Janne 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
25	Cappuzzo F, Magrini E, Ceresoli GL, et al: Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 96:1133–1141. 2004. View Article : Google Scholar
26	Yuan G, Regel I, Lian F, et al: WNT6 is a novel target gene of caveolin-1 promoting chemoresistance to epirubicin in human gastric cancer cells. Oncogene. 32:375–387. 2013. View Article : Google Scholar : PubMed/NCBI
27	Huang X and Guo B: Adenomatous polyposis coli determines sensitivity to histone deacetylase inhibitor-induced apoptosis in colon cancer cells. Cancer Res. 66:9245–9251. 2006. View Article : Google Scholar : PubMed/NCBI
28	Narayan S, Jaiswal AS and Balusu R: Tumor suppressor APC blocks DNA polymerase β-dependent strand displacement synthesis during long patch but not short patch base excision repair and increases sensitivity to methylmethane sulfonate. J Biol Chem. 280:6942–6949. 2005.
29	Fang X, Gu P, Zhou C, et al: β-Catenin overexpression is associated with gefitinib resistance in non-small cell lung cancer cells. Pulm Pharmacol Ther. May 23–2013.(Epub ahead of print).
30	Park SH, Ha SY, Lee JI, et al: Epidermal growth factor receptor mutations and the clinical outcome in male smokers with squamous cell carcinoma of lung. J Korean Med Sci. 24:448–452. 2009. View Article : Google Scholar : PubMed/NCBI
31	Kalikaki A, Koutsopoulos A, Trypaki M, et al: Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC. Br J Cancer. 99:923–929. 2008.
32	Sasaki H, Shimizu S, Endo K, et al: EGFR and erbB2 mutation status in Japanese lung cancer patients. Int J Cancer. 118:180–184. 2006. View Article : Google Scholar : PubMed/NCBI
33	Barber TD, Vogelstein B, Kinzler KW and Velculescu VE: Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med. 351:28832004.PubMed/NCBI
34	Nagahara H, Mimori K, Ohta M, et al: Somatic mutations of epidermal growth factor receptor in colorectal carcinoma. Clin Cancer Res. 11:1368–1371. 2005. View Article : Google Scholar : PubMed/NCBI
35	Park JJ, Yi JY, Jin YB, et al: Sialylation of epidermal growth factor receptor regulates receptor activity and chemosensitivity to gefitinib in colon cancer cells. Biochem Pharmacol. 83:849–857. 2012. View Article : Google Scholar : PubMed/NCBI
36	Milligan SA, Burke P, Coleman DT, et al: The green tea polyphenol EGCG potentiates the antiproliferative activity of c-Met and epidermal growth factor receptor inhibitors in non-small cell lung cancer cells. Clin Cancer Res. 15:4885–4894. 2009. View Article : Google Scholar : PubMed/NCBI
37	den Hartigh JC, van Bergen en Henegouwen PM, Verkleij AJ and Boonstra J: The EGF receptor is an actin-binding protein. J Cell Biol. 119:349–355. 1992.PubMed/NCBI