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.
Highlights
The principal treatment strategy for most cases of ovarian carcinoma is primary cytoreductive surgery and platinum-based chemotherapy, usually using cisplatin or carboplatin along with a taxane (e.g paclitaxel)
To investigate the in vitro expression and subcellular localisation of IL-8RA and IL-8RB protein levels, and the effect of cisplatin treatment on receptor expression, sensitive and resistant ovarian high-grade serous cancer cells were subjected to cisplatin treatment for 24 h and studied by immunofluorescence and confocal microscopy
We previously reported the expression of IL-8 and IL-8 receptors, IL-8RA and IL-8RB, in benign, borderline and malignant epithelial ovarian tumours of different histological subtypes
Summary
The principal treatment strategy for most cases of ovarian carcinoma is primary cytoreductive surgery and platinum-based chemotherapy, usually using cisplatin or carboplatin along with a taxane (e.g paclitaxel). Interleukin-8 (IL-8) is a pro-inflammatory chemokine that is principally a chemoattractant and activator of neutrophils during an immune response [9]. It has cell growth, angiogenic and motogenic effects in different types of malignancies including melanoma, ovarian, prostate, and colon carcinoma [10, 11]. Overexpression of IL-8 in ovarian cancer cells increases anchorage-independent growth, proliferation, angiogenic potential, adhesion and invasion. These effects are decreased on depletion of endogenous IL-8 expression by transfecting IL-8-overexpressing www.impactjournals.com/oncotarget
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