Puerarin inhibits M2 polarization and metastasis of tumor-associated macrophages from NSCLC xenograft model via inactivating MEK/ERK 1/2 pathway

Abstract

Non-small cell lung carcinoma (NSCLC) metastasis is responsible for most of cancer-related mortality. The tumor associated macrophages (TAMs) are known to be crucial cells in lung cancer and are usually divided into two antagonistic types, M1 and M2. Puerarin has a wide spectrum of pharmacological properties. The present study explores puerarin on macrophage polarization and metastasis of NSCLC. The results demonstrated that puerarin inhibited tumor growth and tumor volumes in NSCLC xenograft model, increased M1 markers [CD197+, inducible nitric oxide synthase (iNOS)+, CD40+)] and reduced M2 markers (CD206+, Arg-1+ and CD163+). Besides, puerarin elevated the level of pro-inflammatory cytokine interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-12, decreased the expression of pro-tumor cytokines IL-10, IL-4 and transforming growth factor (TGF)-β. To explore whether puerarin directly acts on macrophages, we purified macrophages from NSCLC model, the results showed that puerarin inhibited macrophages polarized to M2 phenotype and did not require the auxiliary of other cells. In addition, puerarin suppressed the invasion and migration of NSCLC macrophages, restrained the expression of angiogenesis factors. Puerarin also inhibited the activation of mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) 1/2 pathway through inhibition of ERK nucleus translocation. Finally, IL-4 induced M2 macrophage polarization and metastasis were partially offset by puerarin through inactivating the MEK/ERK 1/2 pathway. Taken together, this study validated that puerarin is able to skew macrophage populations back to M1 subsets to stimulate antitumor effects and suggests puerarin is a negative metastatic regulator of NSCLC.

Nanotubular TiO₂ regulates macrophage M2 polarization and increases macrophage secretion of VEGF to accelerate endothelialization via the ERK1/2 and PI3K/AKT pathways

“…M1 macrophages synthesize tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-8, inducible nitric oxide synthase (iNOS), C-C chemokine receptor type 7 (CCR7), and others. 20,21 M2 macrophages produce arginase-1 (ARG1), mannose receptor (CD206), and IL-10 22 as well as vascular endothelial growth factor (VEGF), 23,24 which supports the homing, migration, and proliferation of endothelial cells. 25 Therefore, further studies are needed to investigate the promotion/inhibition of HUVEC behaviors by the mixture secreted by macrophages on the surface of TiO 2 nanotubes.…”

Puerarin inhibits hepatocellular carcinoma invasion and metastasis through miR-21-mediated PTEN/AKT signaling to suppress the epithelial-mesenchymal transition

“…All experimental animals were randomly divided into two groups: control group and puerarin group. The mice in the puerarin group (n=6) were injected with puerarin through the tail vein (40 mg/kg) every other day, while the mice (n=6) in the control group received the same volume injection of phosphate-buffered saline (PBS) (25). Within 45 days, there was no significant difference in the weight of the mice.…”

Application of multifunctional targeting epirubicin liposomes in the treatment of non-small-cell lung cancer

“…12,15 Metastasis is a complicated cell biological procedure that involves decreased adhesion between tumor cells, damages in extracellular matrix structure, movement of tumor cells, and formations of new blood vessels. 16,17 Meanwhile, tumor cells involve coordinated expression of various factors and then produce abundant hydrolytic enzymes that can degrade extracellular matrix and damage basement membrane, thus escaping from the basement membrane and migrating and colonizing in the distant organs. 15,18 It was reported that the inhibition of tumor metastasis could remarkably enhance survival rates of tumor patients.…”