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