Seminal plasma induces angiogenic chemokine expression in cervical cancer cells and regulates vascular function.
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 investigated 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 transactivation of the epidermal growth factor receptor, activation of extracellular signal-regulated kinase and induction 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.
MRC/UCT Research Group for Receptor Biology, Institute of Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, University of Cape Town, South Africa. kurt.sales@uct.ac.za
Kurt J
KJ
Sales
Jason R
JR
Sutherland
Henry N
HN
Jabbour
Arieh A
AA
Katz
D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D054360:Chemokine CXCL1 / Q000235:genetics* / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D012661:Semen / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology*
D043925:Angiogenesis Inducing Agents; C475829:CXCL1 protein, human; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; D017077:Culture Media, Conditioned; D016209:Interleukin-8; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases