cIAP2 upregulated by E6 oncoprotein via epidermal growth factor receptor/phosphatidylinositol 3-kinase/AKT pathway confers resistance to cisplatin in human papillomavirus 16/18-infected lung cancer

• Published in: Clinical cancer research Vol. 16; no. 21; pp. 5200 - 5210
• Main Authors: Wu, Heng-Hsiung, Wu, Jeng-Yuan, Cheng, Ya-Wen, Chen, Chi-Yi, Lee, Ming-Ching, Goan, Yih-Gang, Lee, Huei
• Format: Journal Article
• Language: English
• Published: United States 01.11.2010
• Subjects: Antineoplastic Agents - therapeutic use; Baculoviral IAP Repeat-Containing 3 Protein; Carcinoma, Non-Small-Cell Lung - complications; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - virology; Cisplatin - therapeutic use; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Neoplastic - physiology; Human papillomavirus 16; Human papillomavirus 18; Humans; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Inhibitor of Apoptosis Proteins - physiology; Lung Neoplasms - complications; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - virology; Male; Oncogene Protein v-akt - metabolism; Oncogene Protein v-akt - physiology; Oncogene Proteins, Viral - metabolism; Oncogene Proteins, Viral - physiology; Papillomavirus Infections - complications; Papillomavirus Infections - genetics; Papillomavirus Infections - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol 3-Kinases - physiology; Receptor, Epidermal Growth Factor - metabolism; Receptor, Epidermal Growth Factor - physiology; Repressor Proteins - metabolism; Repressor Proteins - physiology; Ubiquitin-Protein Ligases; Up-Regulation - physiology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-10-0020

Inhibitors of antiapoptosis protein (IAP) have been implicated in the resistance to cisplatin. Therefore, verifying which pathway is involved in cIAP2 upregulation may be helpful in finding a feasible pathway inhibitor to increase the chemotherapeutic efficacy in human papillomavirus (HPV)-infected lung cancer. Specific inhibitors of different pathways were used to verify which pathway is involved in cIAP2 transcription. cIAP2 promoter fragments with various deletions and/or mutations were constructed by site-directed mutagenesis. cIAP2, epidermal growth factor receptor (EGFR), and phospho-AKT (p-AKT) expressions in 136 lung tumors were evaluated by immunohistochemistry. Our data show that two NF-κB (-209 to -200 and -146 to -137) and one CREB (cyclic AMP-responsive element binding protein; -52 to -42) binding sites in cIAP2 promoter region were responsible for cIAP2 upregulated by E6 in TL-1 cells. Moreover, CREB was phosphorylated by EGFR/phosphatidylinositol 3-kinase (PI3K) pathway. To test the involvement of cIAP2 on cisplatin resistance, IC(50) was lowered to 8.6 μmol/L in TL-1 cells with cIAP2 short hairpin RNA (shRNA) transfection and compared with 39.7 μmol/L in TL-1 cells with nonspecific shRNA. Pretreatment with EGFR or PI3K inhibitor in TL-1 cells diminished the resistance to cisplatin. Among the tumor groups, cIAP2 expression correlated significantly with HPV16/18 E6, EGFR, and p-AKT. We followed up 46 of 136 patients who had tumor recurrence and/or metastasis and underwent chemotherapy. Tumors with cIAP2-positive immunostaining were associated with a poorer tumor response to chemotherapy compared with those with negative immunostaining. cIAP2 upregulated by E6 via EGFR/PI3K/AKT cascades may contribute to cisplatin resistance, revealing that the EGFR or PI3K inhibitor combined with cisplatin may improve the chemotherapeutic efficacy in HPV-infected lung cancer.