Abstract
BackgroundApigenin (APG), a natural flavonoid, can affect the development of a variety of tumors, but its role in ovarian cancer remains unclear. There has been an increasing amount of evidence supporting the vital role played by mast cells and the bioactive mediators they release, as components of the tumor microenvironment, in the progression of ovarian cancer (OC); however, the mechanism warrants further exploration.Methods and ResultsIn this study, a combination of transcriptomics analysis and application of TCGA database was performed, and we found that the expression of genes related to mast cell degranulation in ovarian cancer tissues changed remarkably. We then explored whether histamine, a major constituent of mast cell degranulation, could affect the development of ovarian cancer through immunohistochemistry analysis and cell proliferation assays. The results showed that a certain concentration of histamine promoted the proliferation of ovarian cancer cells by upregulating the expression of estrogen receptor α (ERα)/estrogen receptor β (ERβ). Additionally, we found that the inhibition of ERα or the activation of ERβ could inhibit the proliferation of ovarian cancer cells induced by histamine through real-time PCR and western blot assays. Finally, we demonstrated the attenuation effect imparted by apigenin in histamine-mediated ovarian cancer via the PI3K/AKT/mTOR signaling pathway.ConclusionOur research revealed that apigenin decelerated ovarian cancer development by downregulating ER-mediated PI3K/AKT/mTOR expression, thus providing evidence of its applicability as a potentially effective therapeutic agent for ovarian cancer treatment.
Highlights
As one of the most commonly reported cancers among women, ovarian cancer (OC) ranks first in mortality among gynecological tumors, and is characterized by a high recurrence, establishing itself as a grave risk to the lives and health of women worldwide [1]
To investigate the influence of mast cell degranulation on ovarian cancer, the differentially expressed genes between normal ovary tissues and ovarian cancer tissue were analyzed according to the count values of all detected genes (Figure 1A)
Our results indicated that apigenin effectively inhibited the histamine-induced proliferation of OVCAR-3 cells, similar to the effect shown by AZD9496 and DNP treatment (Figure 4B)
Summary
As one of the most commonly reported cancers among women, ovarian cancer (OC) ranks first in mortality among gynecological tumors, and is characterized by a high recurrence, establishing itself as a grave risk to the lives and health of women worldwide [1]. As components of the tumor microenvironment, mast cells (MCs) play a complex role in promoting angiogenesis, tissue remodeling, and in regulating the host immune response by enabling the secretion of proteases to trigger the activation of receptors, prostaglandins, histamine (HA), and other mediators, thereby promoting tumor growth [4]. A considerable number of mast cells were observed in colorectal cancer tissues, and cancer cells near histamine-producing cells were observed to possess a high proliferation ability, and such aspects were found to negatively impact the overall prognosis of patients [10]. There has been an increasing amount of evidence supporting the vital role played by mast cells and the bioactive mediators they release, as components of the tumor microenvironment, in the progression of ovarian cancer (OC); the mechanism warrants further exploration
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