Anticancer activity of dietary xanthone α-mangostin against hepatocellular carcinoma by inhibition of STAT3 signaling via stabilization of SHP1

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers worldwide. The dietary xanthone αmangostin (α-MGT) exhibits potent anti-tumor effects in vitro and in vivo. However, the anti-HCC effects of α-MGT and their underlying mechanisms are still vague. Aberrant activation of signal transducer and activator of transcription 3 (STAT3) is involved in the progression of HCC. We therefore investigated whether α-MGT inhibited the activation of STAT3 and thereby exhibits its anti-HCC effects. In this study, we found that α-MGT significantly suppressed cell proliferation, induced cell cycle arrest, and triggered apoptosis in HCC cells, including HepG2, SK-Hep-1, Huh7, and SMMC-7721 cells in vitro, as well as inhibiting tumor growth in nude mice bearing HepG2 or SK-Hep-1 xenografts. Furthermore, α-MGT potently inhibited the constitutive and inducible activation of STAT3 in HCC cells. In addition, α-MGT also suppressed IL-6-induced dimerization and nuclear translocation of STAT3, which led to inhibition of the expression of STAT3-regulated genes at both mRNA and protein levels. Mechanistically, α-MGT exhibited effective inhibition of the activation of STAT3's upstream kinases, including JAK2, Src, ERK, and Akt. Importantly, α-MGT increased the protein level of Src homology region 2 domain-containing phosphatase-1 (SHP1), which is a key negative regulator of the STAT3 signaling pathway. Furthermore, α-MGT enhanced the stabilization of SHP1 by inhibiting its degradation mediated by the ubiquitin-proteasome pathway. Knockdown of SHP1 using siRNA obviously prevented the α-MGT-mediated inhibition of the activation of STAT3 and proliferation of HCC cells. In summary, α-MGT exhibited a potent anti-HCC effect by blocking the STAT3 signaling pathway via the suppression of the degradation of SHP1 induced by the ubiquitin-proteasome pathway. These findings also suggested the potential of dietary derived α-MGT in HCC therapy.

Alpha-Mangostin Enhances Proliferation in Sorafenib-Surviving HepG2 Liver Cancer Cells by Increasing Anti-Apoptosis and Antioxidant Markers Expressions

“…33 Studies concluded that doses closer to CC50 accentuated pro-oxidant effects. 33,34 In contrast, the study by Hafeez et al showed a dose-dependent decrease in intracellular and extracellular SOR with continued induction of apoptosis in pancreatic cancer cells. The study concluded that the ability to modulate ROS by alpha mangostin depends on the type of cell studied.…”

The effects and mechanism of α‐mangostin on chemosensitivity of gastric cancer cells

“…31 Moreover, α-M could inactivate STAT3, thus exhibiting its antitumor effects on hepatocellular carcinoma. 32 Previously, EBI3 was shown to activate STAT3, thus inducing the proliferation of IL-6-dependent mouse plasmacytoma cells. 33 Here, we reported that the…”

Novel Xanthone Derivatives Impair Growth and Invasiveness of Colon Cancer Cells In Vitro

“…Mangosteen xanthones, especially MAG and GA, have been proven to display significant chemo-preventive and anticancer properties against numerous tumor types [12,[15][16][17][25][26][27]. Moreover, chemical modification of the xanthone structure is believed to further increase the anticancer properties, as described in [28,29].…”