Abstract
α-Mangostin, one of the major constituents of Garcinia mangostana, has been reported to possess several biological activities, including antioxidant, anti-inflammatory, antibacterial, and cytotoxic activities associated with the inhibition of cell proliferation and activation of apoptosis. However, the cellular signaling pathway mediated by α-mangostin has not been firmly established. To investigate the cellular activities of α-mangostin, human cancer cells, MCF-7 and MCF-7-CR cells, were treated with α-mangostin to measure the cellular responses, including cytotoxicity, protein-protein interaction, and protein expression. Cancer cells stably expressed Myc-BCL-XL and HA-MOAP-1 were also included in the studies to delineate the cell signaling events mediated by α-mangostin. Our results showed that the apoptosis signaling mediated by α-mangostin involves the upregulation of endogenous MOAP-1, which interacts with α-mangostin activated BAX (act-BAX) while downregulating the expression of BCL-XL. Moreover, α-mangostin was found to induce BAX oligomerization, the release of mitochondrial cytochrome C, and activation of caspase in MCF-7 cells. In overexpression studies, MCF-7 cells and spheroids stably expressed HA-MOAP-1 and Myc-BCL-XL exhibited differential chemosensitivity toward α-mangostin in which the stable clones expressing HA-MOAP-1 and MYC-BCL-XL were chemosensitive and chemoresistant to the apoptosis signaling events mediated by α-mangostin, respectively, when compared to untreated cells. Together, the data suggest that the cytotoxicity of α-mangostin involves the activation of MOAP-1 tumor suppressor and its interaction with act-BAX, leading to mitochondria dysfunction and cell death.
Highlights
Natural products derived from G. mangostana L. (Clusiaceae) have been used traditionally for wound healing or as antimicrobial and antiparasitic agents to treat dysentery or skin infection in many parts of Asia, including Malaysia, ailand, and China [1,2,3]. e anti-inflammatory property of G.mangostana has been exploited for the treatments of eczema and psoriasis [4,5,6]
To characterize potential novel cell signaling pathways mediated by α-mangostin in cancer cells, MCF-7 and MCF7-CR cells were treated with different concentrations of α-mangostin, and the IC50 and selectivity index values based on the cell viability of α-mangostin-treated cells were determined (Figures 1(a)–1(c)). e cytotoxicity of α-mangostin on MCF-7 spheroid cells was examined (Figures 1(d)-1(e))
To identify the mechanism of apoptosis mediated by α-mangostin, MCF-7 cells were treated with different concentrations of α-mangostin, and the cell lysates were prepared for Western blot analysis with antibodies specific for the proapoptotic and antiapoptotic proteins, including BAX, MOAP-1, and BCL-XL
Summary
Natural products derived from G. mangostana L. (Clusiaceae) have been used traditionally for wound healing or as antimicrobial and antiparasitic agents to treat dysentery or skin infection in many parts of Asia, including Malaysia, ailand, and China [1,2,3]. e anti-inflammatory property of G.mangostana has been exploited for the treatments of eczema and psoriasis [4,5,6]. Natural products derived from G. mangostana L. E anti-inflammatory property of G.mangostana has been exploited for the treatments of eczema and psoriasis [4,5,6]. Phytochemical studies of G.mangostana have identified xanthones as the major constituents, α-mangostin [7,8,9,10]. Natural products derived from G. mangostana are known to exhibit cytotoxic effects on cancer cells [4, 11,12,13,14]. The mechanisms of action of these natural products have not been firmly established. Α-mangostin isolated from G. mangostana has been reported to mediate ROS-associated cytotoxicity [12, 15], apoptosis, anti-inflammatory, and antimicrobial activities [12, 16]. Α-mangostin has been shown to inhibit the expression of MMP2 and MMP9 and to promote the release of endonuclease-G from mitochondria through caspase-independent apoptosis [12, 14, 17]
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