The role of interleukin-8 (IL-8) and IL-8 receptors in platinum response in high grade serous ovarian carcinoma

• Published in: Oncotarget 2015-10, Vol.6 (31), p.31593-31603
• Main Authors: Stronach, Euan A, Cunnea, Paula, Turner, Christina, Guney, Tankut, Aiyappa, Radhika, Jeyapalan, Senthuran, de Sousa, Camila H, Browne, Alacoque, Magdy, Nesreen, Studd, James B, Sriraksa, Ruethairat, Gabra, Hani, El-Bahrawy, Mona
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; bcl-Associated Death Protein - metabolism; Cell Line, Tumor; Cisplatin - pharmacology; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Interleukin-8 - genetics; Interleukin-8 - metabolism; Neoplasm Grading; Neoplasms, Cystic, Mucinous, and Serous - drug therapy; Neoplasms, Cystic, Mucinous, and Serous - genetics; Neoplasms, Cystic, Mucinous, and Serous - metabolism; Neoplasms, Cystic, Mucinous, and Serous - pathology; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Phosphorylation; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptors, Interleukin-8A - antagonists & inhibitors; Receptors, Interleukin-8A - genetics; Receptors, Interleukin-8A - metabolism; Receptors, Interleukin-8B - antagonists & inhibitors; Receptors, Interleukin-8B - genetics; Receptors, Interleukin-8B - metabolism; Research Paper; RNA Interference; Signal Transduction - drug effects; Time Factors; Transfection
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3415

Platinum based drugs are the cornerstone of chemotherapy for ovarian cancer, however the development of chemoresistance hinders its success. IL-8 is involved in regulating several pro-survival pathways in cancer. We studied the expression of IL-8 and IL-8 receptors in platinum sensitive and resistant cell lines. Using qRT-PCR and immunohistochemistry, both platinum sensitive (PEA1, PEO14) and resistant (PEA2, PEO23) show increased expression of IL-8 and IL-8 receptors. IL-8RA shows nuclear and cytoplasmic expression, whilst IL-8RB is present solely in the cytoplasm. Knockdown of IL-8 increased sensitivity to cisplatin in platinum sensitive and reversed platinum resistance in resistant cell lines, decreased the expression of anti-apoptotic Bcl-2 and decreased inhibitory phosphorylation of pro-apoptotic Bad. IL-8 receptor antagonist treatment also enhanced platinum sensitivity. Nuclear localisation of IL-8RA was only detected in platinum resistant tumours. Inhibition of IL-8 signalling can enhance response in platinum sensitive and resistant disease. Nuclear IL-8RA may have potential as a biomarker of resistant disease.