Seminal plasma induces angiogenic chemokine expression in cervical cancer cells and
regulates vascular function
Kurt J. Salesa,⁎,1, Jason R. Sutherlanda,1, Henry N. Jabbourb, Arieh A. Katza,⁎
aMRC/UCTResearch Group for ReceptorBiology,Institute of Infectious Disease and Molecular Medicine and Division ofMedicalBiochemistry, Faculty ofHealthSciences,University of Cape Town,
7925, South Africa
bMRC Human Reproductive Sciences Unit, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, EH16 4TJ, UK
a b s t r a c ta r t i c l ei n f o
Received 24 April 2012
Received in revised form 14 June 2012
Accepted 15 June 2012
Available online 23 June 2012
Cervical cancer is one of the leading gynecological malignancies in women. We have recently shown that
seminal plasma (SP) can regulate the inflammatory cyclooxygenase-prostaglandin pathway and enhance
the growth of cervical epithelial tumours in vivo by promoting cellular proliferation and alteration of vascular
function. This study investigated the molecular mechanism whereby SP regulates vascular function using an
in vitro model system of HeLa cervical adenocarcinoma cells and human umbilical vein endothelial cells
(HUVECs). We found that SP rapidly enhanced the expression of the angiogenic chemokines, interleukin
(IL)-8 and growth regulated oncogene alpha (GRO) in HeLa cells in a time-dependent manner. We investigat-
ed the molecular mechanism of SP-mediated regulation of IL-8 and GRO using a panel of chemical inhibitors
of cell signalling. We found that treatment of HeLa cells with SP elevated expression of IL-8 and GRO by trans-
activation of the epidermal growth factor receptor, activation of extracellular signal-regulated kinase and in-
duction of cyclooxygenase enzymes and nuclear factor kappa B. We investigated the impact of IL-8 and GRO,
released from HeLa cells after treatment with SP, on vascular function using a co-culture model system of
conditioned medium (CM) from HeLa cells, treated with or without SP, and HUVECs. We found that CM
from HeLa cells induced the arrangement of endothelial cells into a network of tube-like structures via the
CXCR2 receptor on HUVECs. Taken together our data outline a molecular mechanism whereby SP can alter
vascular function in cervical cancers via the pro-angiogenic chemokines, IL-8 and GRO.
© 2012 Elsevier B.V. All rights reserved.
Chronic inflammation has been linked to increased cancer risk in
numerous organs including the liver and colon [1,2]. Non-steroidal
anti-inflammatory drug use and suppression of the inflammatory cy-
clooxygenase (COX)-prostaglandin (PG) axis have been shown over
the last two decades to have beneficial effects in reducing inflamma-
tion and have been associated with an inverse risk of developing can-
cer. These observations have been confirmed by recent clinical trials
that have shown that long term aspirin treatment can be beneficial
for reducing the burden of colorectal cancer .
In sub-Saharan African countries, cancer of the uterine–cervix is
the leading gynecological malignancy [4,5]. The main etiological fac-
tor associated with cervical cancer is infection of the cervix by
human papillomavirus (HPV) . Following infection, HPV oncogenes
have been shown to regulate the COX-PG axis in cervical cancer cells
to promote inflammation, persistent infection and tumorigenesis
[7,8]. We and others have shown that the inflammatory COX-PG
axis is elevated in cervical cancers . COX enzymes, of which there
are two isoforms in humans, namely COX-1 and COX-2, catalyse the
rate limiting conversion of arachidonic acid to PG . Following
their biosynthesis, PG are actively transported from the cell, where
they act locally in an autocrine/paracrine manner via PG receptors
. We have shown that PG, biosynthesised following induction of
COX-1 and COX-2 in cervical adenocarcinoma cells, elevates the ex-
pression of potent pro-angiogenic factors such as basic fibroblast
growth factor 2 (FGF2), vascular endothelial growth factor (VEGF)
and angiopoietins [9,10]. Following their biosynthesis and release
from neoplastic cervical epithelial cells, angiogenic factors can then
exert a paracrine activity on endothelial cells to enhance blood supply
via angiogenesis to facilitate tumour growth . These observations
have led us to propose that suppression of the inflammatory COX-PG
axis with affordable non-steroidal anti-inflammatory drugs like aspi-
rin could be beneficial for preventing cervical cancer progression in
resource-poor countries in Africa, by suppressing potent inflammato-
ry and angiogenic pathways that can promote disease progression.
Biochimica et Biophysica Acta 1823 (2012) 1789–1795
⁎ Corresponding authors at: MRC/UCT Research Group for Receptor Biology, Room
N.2.02 Wernher and Beit North, Institute of Infectious Disease and Molecular Medicine
and Division of Medical Biochemistry, UCT Faculty of Health Sciences, Observatory
7925, South Africa.
E-mail addresses: email@example.com (K.J. Sales), firstname.lastname@example.org (A.A. Katz).
1These authors contributed equally to this work.
0167-4889/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
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the study design; nor in the collection, analysis and interpretation of
data; or in the writing of the report; or the decision to submit the
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