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.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Wu
Heng-Hsiung
HH
Institute of Medical and Molecular Toxicology, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China.
Wu
Jeng-Yuan
JY
Cheng
Ya-Wen
YW
Chen
Chi-Yi
CY
Lee
Ming-Ching
MC
Goan
Yih-Gang
YG
Lee
Huei
H
D000970:Antineoplastic Agents / Q000627:therapeutic use; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D002945:Cisplatin / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D052162:Human papillomavirus 16; D052161:Human papillomavirus 18; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008175:Lung Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D008297:Male; D051058:Oncogene Protein v-akt / Q000378:metabolism / Q000502:physiology*; D009856:Oncogene Proteins, Viral / Q000378:metabolism / Q000502:physiology*; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation / Q000502:physiology
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; D051034:Inhibitor of Apoptosis Proteins; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D002945:Cisplatin