The role of interleukin-8 (IL-8) and IL-8 receptors in platinum response in high grade serous ovarian carcinoma.
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.
Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
Euan A
EA
Stronach
Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
Paula
P
Cunnea
Department of Histopathology, Imperial College London, Hammersmith Hospital, London, UK.
Christina
C
Turner
Department of Histopathology, Imperial College London, Hammersmith Hospital, London, UK.
Tankut
T
Guney
Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
Radhika
R
Aiyappa
Department of Histopathology, Imperial College London, Hammersmith Hospital, London, UK.
Senthuran
S
Jeyapalan
Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
Camila H
CH
de Sousa
Department of Histopathology, Imperial College London, Hammersmith Hospital, London, UK.
Alacoque
A
Browne
Department of Histopathology, Imperial College London, Hammersmith Hospital, London, UK.|Department of Pathology, National Cancer Institute, Cairo University, Egypt.
Nesreen
N
Magdy
Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
James B
JB
Studd
Epigenetics Group, International Agency for Research on Cancer, Lyon, France.
Ruethairat
R
Sriraksa
Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
Hani
H
Gabra
Department of Histopathology, Imperial College London, Hammersmith Hospital, London, UK.|Department of Pathology, Faculty of Medicine, University of Alexandria, Egypt.
Mona
M
El-Bahrawy
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D051025:bcl-Associated Death Protein / Q000378:metabolism
C494819:BAD protein, human; C000595707:BCL2 protein, human; C508606:CXCL8 protein, human; D016209:Interleukin-8; D019253:Proto-Oncogene Proteins c-bcl-2; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D051025:bcl-Associated Death Protein; D002945:Cisplatin
carcinoma; chemoresistance; cytokine; interleukin-8; ovary