Follicle-stimulating hormone promotes the proliferation of epithelial ovarian cancer cells by activating sphingosine kinase

Abstract

follicle-stimulating hormone (fSH) is closely related to the pathogenesis and progression of epithelial ovarian cancer (EOC). However, until now, knowledge relating to FSH-driven signalling pathways that lead to the growth of EOC remained incomplete. We sought to explore whether sphingosine kinase (SphK) could mediate fSH-induced ovarian cancer cell proliferation and which pathway might be involved in this process. The expression of phospho-SphK1 and phospho-SphK2 was detected in sections of EOC tissues by Immunohistochemical staining, and clinical significances were analyzed by statistical analysis. EOC cells were treated with FSH or/and SKI-II. CCK8 assays and colony formation assays were used to investigate cell proliferation. Western blot was carried out to detect protein expression in EOC cell line after treated with FSH. Here, for the first time, we provide evidence that high expression levels of phospho-SphK1 and phospho-SphK2 were both prognostic indicators of overall survival (OS) in EOC. Additionally, the expression levels of both phospho-SphK1 and phospho-SphK2 were closely correlated with the expression level of follicle-stimulating hormone receptor (FSHR) in ovarian cancer tissues. FSH stimulated the phosphorylation of both SphK1 and SphK2 and was able to regulate the survival and growth of ovarian cancer cells by activating SphK1 and SphK2 through ERK1/2. Both isoenzymes of SphK were equally responsible for FSH-induced cell proliferation of EOC. Both Erk1/2 and Akt activation play important roles in mediating FSH-induced cell proliferation after phosphorylation of SphK. Moreover, our data demonstrated that S1P receptor 1 (S1PR1) and S1PR3, key components of the SphK signalling system, were involved in FSH-mediated proliferation of EOC. Taken together, the results of the current study revealed that SphK is an essential mediator in FSH-induced proliferation of ovarian cancer cells in EOC, which indicates a new signalling pathway that controls fSH-mediated growth in eoc and suggests a new strategy that pharmaceutically targets both isoenzymes of SphK for the management of ovarian cancer.

Activation of SphK1 by adipocytes mediates epithelial ovarian cancer cell proliferation

“…We focused on SphK1 because it plays important roles in signal transmission and cancer proliferation [ 5 , 6 ]. SphK1 overexpression promoted the proliferation of several types of cancer, including ovarian, breast and colon cancer [ 10 , 21 , 22 ]. Moreover, blockade of SphK1 inhibited growth in several tumour types, including breast, colon and thyroid cancer [ 22 – 24 ].…”

“…The activation of the ERK pathway is recognized as a key cellular phenomenon that initiates and facilitates cell proliferation [ 25 , 26 ]. ERK activation in EOC cells promoted cell proliferation, and blocking ERK activation inhibited EOC growth [ 10 , 27 ]. Adi-CM significantly promoted EOC cell proliferation.…”

“…Therefore, we investigated the role of adipocytes in ERK activation and found that Adi-CM activated ERK through ERK phosphorylation in EOC. Previously, we demonstrated that ERK is a downstream target of SphK1 in EOC [ 10 , 12 ]. Having shown the ability of adipocytes to activate SphK1, a potential role of SphK1 in adipocyte-induced ERK activation was suggested.…”

“…Its activation was reported to contribute to the survival, proliferation, migration, invasion, and drug resistance of various cancer types [ 5 – 7 ]. We previously showed that SphK1, which is overexpressed in EOC tissue [ 8 ], is required for EOC metastasis and angiogenesis [ 8 , 9 ] and that its activation is inversely correlated with survival in EOC patients [ 10 ]. Although SphK1 is a significant signalling enzyme in EOC progression, its regulatory mechanisms are unclear.…”

A Comprehensive Molecular and Clinical Analysis of the piRNA Pathway Genes in Ovarian Cancer

“…In addition, induction of PIWIL2 was also reported to endow cancer stem cell-like properties to human fibroblasts with ectopic expression of these stemness markers [90]. While there are many papers on FSH causing OC proliferation and migration [4,[92][93][94][95], there is a study claiming FSH as having protective properties against cancer [96]. Therefore, further investigation is needed to identify the relationship between FSH and PIWIL2 and whether they contribute to or against the development of HGSOC.…”