Abstract
BackgroundFatty acid synthase (FAS) has been proven over-expressed in human breast cancer cells and consequently, has been recognized as a target for breast cancer treatment. Alpha-mangostin, a natural xanthone found in mangosteen pericarp, has a variety of biological activities, including anti-cancer effect. In our previous study, alpha-mangostin had been found both fast-binding and slow-binding inhibitions to FAS in vitro. This study was designed to investigate the activity of alpha-mangostin on intracellular FAS activity in FAS over-expressed human breast cancer cells, and to testify whether the anti-cancer activity of alpha-mangostin may be related to its inhibitory effect on FAS.MethodsWe evaluated the cytotoxicity of alpha-mangostin in human breast cancer MCF-7 and MDA-MB-231 cells. Intracellular FAS activity was measured by a spectrophotometer at 340 nm of NADPH absorption. Cell Counting Kit assay was used to test the cell viability. Immunoblot analysis was performed to detect FAS expression level, intracellular fatty acid accumulation and cell signaling (FAK, ERK1/2 and AKT). Apoptotic effects were detected by flow cytometry and immunoblot analysis of PARP, Bax and Bcl-2. Small interfering RNA was used to down-regulate FAS expression and/or activity.ResultsAlpha-mangostin could effectively suppress FAS expression and inhibit intracellular FAS activity, and result in decrease of intracellular fatty acid accumulation. It could also reduce cell viability, induce apoptosis in human breast cancer cells, increase in the levels of the PARP cleavage product, and attenuate the balance between anti-apoptotic and pro-apoptotic proteins of the Bcl-2 family. Moreover, alpha-mangostin inhibited the phosphorylation of FAK. However, the active forms of AKT, and ERK1/2 proteins were not involved in the changes of FAS expression induced by alpha-mangostin.ConclusionsAlpha-mangostin induced breast cancer cell apoptosis by inhibiting FAS, which provide a basis for the development of xanthone as an agent for breast cancer therapy.
Highlights
Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer death among women in both developed and developing nations
We investigated the possible pathways that involved in the modulation of Fatty acid synthase (FAS) by αmangostin, and found that α-mangostin could effectively suppress FAS expression and inhibit intracellular FAS activity, resulted in decrease of intracellular fatty acid accumulation. α-Mangostin could reduce cell viability and induce apoptosis in human breast cancer cells
The cytotoxicity of α-mangostin in breast cancer cells To evaluate the cytotoxicity of α-mangostin, breast cancer cells were incubated with various concentrations of αmangostin (0, 1, 2, 3, 4, 6, 8, 10 μM) for 24 and 48 h followed by a Cell counting kit (CCK-8) assay
Summary
Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer death among women in both developed and developing nations. The high expression of FAS in human cancer and its association with poorer prognoses in breast [3], ovarian [4] and prostate carcinomas [5] suggest that high levels of FAS expression and activity provide an advantage for tumor growth and progression. This is different from the role of FAS-. This study was designed to investigate the activity of alpha-mangostin on intracellular FAS activity in FAS over-expressed human breast cancer cells, and to testify whether the anti-cancer activity of alpha-mangostin may be related to its inhibitory effect on FAS
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