Abstract
Epithelial ovarian cancer (EOC) is the leading cause of deaths due to cancer in women. Adipocytes have been suggested to play a key role in the stimulation of EOC growth. However, the mechanisms underlying the adipocyte-induced EOC proliferation remain undefined. Here, we provide the first evidence that adipocytes induce the activation of sphingosine kinase (SphK) 2 in EOC, which represents a novel pathway that mediates the adipocyte-induced EOC growth. SphK2 inhibition in EOC cells led to a remarkable inhibition of the adipocyte-induced cell proliferation. Moreover, the adipocyte-induced SphK2 activation in EOC cells was extracellular signal-regulated protein kinases (ERK) dependent. Furthermore, silencing SphK2 in EOC significantly inhibited the adipocyte-induced expression of phospho-ERK and c-Myc, two crucial players in EOC growth. Collectively, the current study unraveled a previously unrecognized role of SphK2 in the adipocyte-induced growth-promoting action in EOC, suggesting a novel target for EOC treatment.
Highlights
Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy [1]
3.1 SphK2 contributes to the adipocyteinduced EOC cell proliferation
SphK2 contributes to the adipocyte-induced extracellular signal-regulated protein kinases (ERK) and c-Myc pathway activation, both of which are well recognized as key signals that facilitate EOC growth
Summary
Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy [1]. Most EOC patients are found to have tumors in an advanced stage at initial diagnosis, which may lead to high disease mortality [2]. Understanding the mechanisms that regulate EOC growth may have an important impact on the outcome of this fatal cancer. EOC growth is affected by adipocytes [3,4,5,6,7]. EOC cells have a predilection to proliferate in the omentum, an organ primarily composed of adipocytes [3,6,7]. Coculture of EOC cells with adipocytes can promote the proliferation of EOC. As a source of various adipokines, adipocytes can provide high-energy metabolites and a series of factors for EOC growth [5,8]. The molecular mechanisms responsible for the growth-promoting effect of adipocytes in EOC remain unclear
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