Tumour‐associated macrophage (TAM) is an important component in tumour microenvironment. Generally, TAM exhibits the function of M2‐like macrophage, which was closely related to angiogenesis and tumour progression. Dioscin, a natural steroidal saponin, has shown its powerful anti‐tumour activity recently. However, the mechanism of dioscin involved in immune regulation is still obscure. Here, we observed dioscin induced macrophage M2‐to‐M1 phenotype transition in vitro and inhibited IL‐10 secretion. Meanwhile, the phagocytosis of macrophages was enhanced. In subcutaneous lung tumour models, dioscin inhibited the augmentation of M2 macrophage populations. Furthermore, dioscin down‐regulated STAT3 and JNK signalling pathways in macrophages in vitro. In BMDMs, activating JNK and inhibiting STAT3 induce macrophages to M1 polarization while inhibiting JNK and activating STAT3 to M2 polarization. Additionally, condition mediums from dioscin‐pre‐treated macrophages inhibited the migration of 3LL cells and the tube‐formation capacity of HUVECs. What's more, dioscin‐mediated macrophage polarization inhibited the in vivo metastasis of 3LL cells. In conclusion, dioscin may act as a new anti‐tumour agent by inhibiting TAMs via JNK and STAT3 pathways in lung cancer.

Lung squamous cell carcinoma (SCC) is one of the deadliest cancers both in China and worldwide. To date, the efficacy of lung SCC treatments is limited. Recent studies have elucidated the powerful anti-tumour role of dioscin in different human cancers. Here, our study aims to investigate the effect of dioscin on lung SCC and its underlying mechanism. First, we found that dioscin not only inhibited cell proliferation and cell migration and induced cell apoptosis in lung SCC cells but also suppressed tumour growth in tumour-bearing mice. Furthermore, we noted that the accumulation of intracellular reactive oxygen species (ROS) was triggered by dioscin in lung SCC cells, leading to the phosphorylation of HSP27 through p38-MAPK and consequent cell apoptosis. The activation of p38-MAPK/HSP27 induced by the p38-MAPK activator Anisomycin enhanced the apoptosis of lung SCC cells, while the ROS inhibitor N-acetyl-L-cysteine (NAC) and the p38-MAPK inhibitor SB203580 both attenuated dioscin-mediated cell apoptosis. Moreover, NAC suppressed the activation of p38-MAPK/HSP27 that induced by dioscin. In conclusion, these results confirm that dioscin facilitates ROS-induced apoptosis via the p38-MAPK/HSP27-mediated pathway in lung SCC.

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Lung squamous cell carcinoma (SCC) accounts for a considerable proportion of lung cancer cases, but there is still a lack of effective therapies. FGFR1 amplification is generally considered a promising therapeutic target. Honokiol is a chemical compound that has been proven to be effective against various malignancies and whose analog has been reported to target the mitogen‐activated protein kinase family, members of a downstream signaling pathway of FGFR1. This was an explorative study to determine the mechanism of honokiol in lung SCC. We found that honokiol induced apoptosis and cell cycle arrest in lung SCC cell lines in a time‐ and dose‐dependent manner. Honokiol also restricted cell migration in lung SCC cell lines. Moreover, the expression of FGF2 and the activation of FGFR1 were both downregulated by honokiol. Pharmacological inhibition and siRNA knockdown of FGFR1 induced apoptosis in lung SCC cells. Our in vivo study indicated that honokiol could suppress the growth of xenograft tumors, and this effect was associated with the inhibition of the FGF2‐FGFR1 signaling pathway. In conclusion, honokiol induced cell apoptosis in lung SCC by targeting the FGF2‐FGFR1 autocrine loop.

The interaction of immune cells and cytokines in the tumor microenvironment affects the development and prognosis of tumors with an unclear potential regulatory mechanism. Recent studies have elucidated the protumor role of Th22 cells and its lineage-specific cytokine IL-22 in different human cancers. The present study is aimed at investigating the biological effect of Th22 cells/IL-22 and its molecular mechanism in the pathogenesis process of non-small-cell lung cancer (NSCLC). It was initially found that Th22 cells were enriched in the peripheral blood of NSCLC patients. The level of Th22 cells in peripheral blood mononuclear cells (PBMCs) was positively correlated with the TNM stage, lymph node metastasis, and clinical tumor biomarkers. Furthermore, IL-22 not only antagonized the apoptosis inducing and cell cycle arresting effect by chemotherapy and molecular targeted drugs on NSCLC cell lines but also promoted tumor cell proliferation and tumor tissue growth. Moreover, IL-22 activated the JAK-STAT3/MAPK/AKT signaling pathway, both in vitro and in vivo. Conclusively, the present results confirm that Th22 cells/IL-22 may serve as a negative immune regulator in lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most common malignancies with high morbidity and mortality. PKHB1, a serum-stable Thrombospondin-1 (TSP-1) mimic peptide, has shown some effective ability in triggering cell death against several cancers. Here, we aimed to study the potential biological function of PKHB1 and its molecular mechanism in NSCLC. Our results revealed that PKHB1 significantly suppressed NSCLC cell proliferation, cell migration, and induced apoptosis in a dose-dependent manner. Additionally, we found that PKHB1 treatment resulted in mitochondrial transmembrane potential depolarization, Ca 2+ overloading as well as the upregulation of proapoptotic proteins. Mechanistically, PKHB1 induced NSCLC cells apoptosis in a CD47-independent manner. Further study revealed that PKHB1 provoked endoplasmic reticulum (ER) stress principally through the activation of CHOP and JNK signaling, which could be alleviated in the presence of 4-PBA, an ER stress inhibitor. Furthermore, xenograft tumor models showed that PKHB1 treatment could notably inhibit NSCLC tumor growth in vivo. In conclusion, these findings suggested that PKHB1 exerted antitumor efficacy in NSCLC via triggering ER stress-mediated but CD47-independent apoptosis, potentially functioned as a promising peptide-based therapeutic agent for NSCLC.

Background: Several reports from different groups suggest that novel KRAS inhibitors are not effective ex vivo, but the mechanism(s) responsible for this are unknown. We performed complex experiments that highlight the huge discrepancy between the marked in vivo and the minimal in vitro effects of KRAS inhibitors. Furthermore, we identified and validated the mechanism of the in vivo-restricted actions of KRAS inhibitors in immunocompetent mice, which can be translated to successful new treatments for patients with KRAS-mutant cancers. Method: We treated tumor cells with defined KRAS mutation status with KRAS inhibitors deltarasin, cysmethynil, and AA12 and used different in vitro assays as readout. Additionally, KRAS silencing and overexpression were done using shRNA and KRAS G12C vectors and included in the experimental setup. In parallel C57BL/6 wildtype mice or deficient in interleukin (IL)-1b (Il1b-/-) or chemokine receptors (Ccr2-/-, Cxcr1-/-, Cxcr2+/-) received s.c. KRAS-mutant or wild-type tumor cells followed by saline or deltarasin treatments. Microarrays were done using a large set of Kras-mutant and Kras-wildtype cell lines. Result: We identified that KRAS inhibitors exerted comparable effects against cancer cells in vitro irrespective of KRAS status. However, mice only with KRAS-mutant tumors responded selectively to deltarasin treatment. Similar in vivo-restricted effects were evident after genetic manipulation of KRAS. Microarrays identified a 42-gene signature specific to Kras-mutant cancer cells and responsive to Kras manipulation, which contained Kras, Ccl2, Il1r1, Ccl7, and Cxcl1. Deltarasin was effective in halting KRAS-mutant flank tumors in Wt, Cxcr1-/-, and Cxcr2+/-, but not in Ccr2-/-and Il1b-/-mice. qPCR results revealed a strong regulation of Il1r1/IL1R1 mRNA expression depending of Kras/ KRAS mutation status and drug treatment. Thereby, KRAS inhibition can be effective in vivo via blockade of the positive feedback loop of KRAS-CCL2-IL1ß. Conclusion: Inflammatory signaling loops are synthetic lethality targets for KRAS mutant tumors and only druggable by KRAS inhibitors in vivo. Hence in vitro drug screens may be suboptimal settings for anti-KRAS drug discovery.