Astragaloside IV inhibits lung cancer progression and metastasis by modulating macrophage polarization through AMPK signaling

Abstract

BackgroundAccumulating evidence suggests that M2-polarized tumor-associated macrophages (TAMs) play an important role in cancer progression and metastasis, making M2 polarization of TAMs an ever more appealing target for therapeutic intervention. Astragaloside IV (AS-IV), a saponin component isolated from Astragali radix, has been reported to inhibit the invasion and metastasis of lung cancer, but its effects on TAMs during lung cancer progression have not been investigated.MethodsHuman THP-1 monocytes were induced to differentiate into M2 macrophages through treatments with IL-4, IL-13, and phorbol myristate acetate (PMA). We used the lung cancer cell lines A549 and H1299 cultured in conditioned medium from M2 macrophages (M2-CM) to investigate the effects of AS-IV on tumor growth, invasion, migration, and angiogenesis of lung cancer cells. Macrophage subset distribution, M1 and M2 macrophage-associated markers, and mRNA expression were analyzed by flow cytometry and quantitative PCR. The activation of adenosine monophosphate-activated protein kinase (AMPK) signaling pathways that mediate M2-CM–promoted tumor migration was detected using western blotting.ResultsHere we found that AS-IV significantly inhibited IL-13 and IL-4–induced M2 polarization of macrophages, as illustrated by reduced expression of CD206 and M2-associated genes, and that AS-IV suppressed the M2-CM–induced invasion, migration, and angiogenesis of A549 and H1299 cells. In vivo experiments demonstrated that AS-IV greatly inhibited tumor growth and reduced the number of metastases of Lewis lung cancer. The percentage of M2 macrophages was decreased in tumor tissue after AS-IV treatment. Furthermore, AS-IV inhibited AMPKα activation in M2 macrophages, and silencing of AMPKα partially abrogated the inhibitory effect of AS-IV.ConclusionsAS-IV reduced the growth, invasion, migration, and angiogenesis of lung cancer by blocking the M2 polarization of macrophages partially through the AMPK signaling pathway, which appears to play an important role in AS-IV’s ability to inhibit the metastasis of lung cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0878-0) contains supplementary material, which is available to authorized users.

Antiangiogenesis Roles of Exosomes with Fei‐Liu‐Ping Ointment Treatment are Involved in the Lung Carcinoma with the Lewis Xenograft Mouse Model

“…Many of the herbal medicine components in FLP ointment have antitumour effects. For example, ginsenoside Rg3 (Radix Panacis Quinquefolii) inhibits tumour migration and invasion through the PI3K-AKT signalling pathway [44] and may improve the sensitivity to cisplatin during lung cancer therapy [45]; liquiritin (Radix Glycyrrhizae) induces apoptotic cell death by upregulating p53 and p21 in A549 non-small cell lung cancer cells [46]; and calycosin, astragaloside VI, and formononetin (Radix Astragali) suppress A549 cell proliferation and migration through the induction of cell cycle arrest and apoptosis via the PKC-α/ERK1/2 pathway and the modulation of macrophage polarization through AMPK signalling [47][48][49]. us, these components are the basis for the inhibitory functions in lung cancer.…”

M2‐polarized tumor‐associated macrophages promote epithelial‐mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma

“…M2‐TAMs which are differentiated from THP‐1 cells have been extensively used to study M2‐polarized macrophage functions . THP‐1 cells were maintained in culture in Roswell Park Memorial Institute 1640 (RPMI 1640; Gibco, Invitrogen) culture medium containing 10% of fetal bovine serum (FBS; Gibco, Invitrogen) and supplemented with 2 mM l ‐glutamine (Sigma) at 37°C in a humidified atmosphere of 5% CO 2 .…”

“…2 | MATERIALS AND METHODS 2.1 | Cell culture and experimental treatments M2-TAMs which are differentiated from THP-1 cells have been extensively used to study M2-polarized macrophage functions. [12][13][14][15][16][17] THP-1 cells were maintained in culture in Roswell Park Memorial Institute 1640 (RPMI 1640; Gibco, Invitrogen) culture medium containing 10% of fetal bovine serum (FBS; Gibco, Invitrogen) and supplemented with 2 mM L-glutamine (Sigma) at 37°C in a humidified atmosphere of 5% CO 2 . To generate M2-TAMs, 1 × 10 6 THP-1 cells were treated with 100 ng/mL phorbol 12-myristate 13-acetate (PMA; MedChemExpress) for 24 hours, then incubated with 20 ng/mL interleukin-4 (IL-4; Novus Biologicals) for 48 hours.…”

The Roles of AMPK in Revascularization

“…Furthermore, antifungal drug itraconazole targets mitochondrial protein voltage-dependent anion channel 1 (VDAC1) to suppress angiogenesis by modulating the AMPK/mTOR signaling axis in endothelial cells [123]. Interestingly, there are some studies which have shown that AMPK activation by some agents may play a positive role in tumor growth, even including metformin [124,125].…”