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

Euan A Stronach; Paula Cunnea; Christina Turner; Tankut Guney; Radhika Aiyappa; Senthuran Jeyapalan; Camila H de Sousa; Alacoque Browne; Nesreen Magdy; James B Studd; Ruethairat Sriraksa; Hani Gabra; Mona El-Bahrawy

doi:10.18632/oncotarget.3415

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

Oncotarget. 2015 Oct 13;6(31):31593-603. doi: 10.18632/oncotarget.3415.

Authors

Affiliations

¹ Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
² Department of Histopathology, Imperial College London, Hammersmith Hospital, London, UK.
³ Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
⁴ Department of Pathology, National Cancer Institute, Cairo University, Egypt.
⁵ Epigenetics Group, International Agency for Research on Cancer, Lyon, France.
⁶ Department of Pathology, Faculty of Medicine, University of Alexandria, Egypt.

Abstract

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.

Keywords: carcinoma; chemoresistance; cytokine; interleukin-8; ovary.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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
RNA Interference
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*
Signal Transduction / drug effects
Time Factors
Transfection
bcl-Associated Death Protein / metabolism

Substances

BAD protein, human
BCL2 protein, human
CXCL8 protein, human
Interleukin-8
Proto-Oncogene Proteins c-bcl-2
Receptors, Interleukin-8A
Receptors, Interleukin-8B
bcl-Associated Death Protein
Cisplatin

Grants and funding

001/WHO_/World Health Organization/International