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Pulmonary fibrosis (PF) is chronic and irreversible damage to the lung characterized by fibroblast activation and matrix deposition. Although recently approved novel anti‐fibrotic agents can improve the lung function and survival of patients with PF, the overall outcomes remain poor. In this study, a novel imidazopurine compound, 3‐(2‐chloro‐6‐fluorobenzyl)‐1,6,7‐trimethyl‐1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione (IM‐1918), markedly inhibited transforming growth factor (TGF)‐β‐stimulated reporter activity and reduced the expression of representative fibrotic markers, such as connective tissue growth factor, fibronectin, collagen and α‐smooth muscle actin, on human lung fibroblasts. However, IM‐1918 neither decreased Smad‐2 and Smad‐3 nor affected p38MAPK and JNK. Instead, IM‐1918 reduced Akt and extracellular signal‐regulated kinase 1/2 phosphorylation increased by TGF‐β. Additionally, IM‐1918 inhibited the phosphorylation of fibroblast growth factor receptors 1 and 3. In a bleomycin‐induced murine lung fibrosis model, IM‐1918 profoundly reduced fibrotic areas and decreased collagen and α‐smooth muscle actin accumulation. These results suggest that IM‐1918 can be applied to treat lung fibrosis. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) is a commonly used treatment option for patients with cancer because it can effectively control tumor growth and kill tumor cells. However, the impact of RT goes beyond direct tumor cell killing because it can change the tumor microenvironment by altering surrounding tissues and infiltrating cells and modulating the expression of immune checkpoints. Poliovirus receptor (PVR, cluster of differentiation (CD)155), a member of the nectin-like molecule family, is overexpressed in many human cancers. However, its role in the tumor growth and T-cell immune responses of triple-negative breast cancer (TNBC) remains unclear. In the present study, we observe that radiation exposure increases PVR expression in MDA-MB-231 and BT549 cells. Silencing PVR not only inhibited the proliferation of breast cancer cells but also significantly enhanced the cytotoxicity of cytotoxic T lymphocytes (CTLs) compared with the control or RT groups. Treatment of T cells with PVR decreased CD8 + T cells, increased CD4 + T cells, and induced PVR ligands such as T cell immunoreceptor with immunoglobulin and ITIM domain, CD226, and CD96. However, after treatment with PVR, CTL responses decreased and secretion of interferon-γ, tumor necrosis factor-α, interleukin (IL)-2, IL-6, and IL-10 was significantly inhibited. In contrast, PVR knockdown increased the production of these cytokines, illustrating the immunosuppressive function of PVR. Suppression of PVR using an anti-PVR antibody inhibited 4T1 tumor growth by increasing immune cell infiltration. These results provide new insights into the role of PVR in TNBC and highlight its potential as a target for T cell-mediated immunotherapy in breast cancer., Competing Interests: None., (AJCR Copyright © 2023.)

The survival and death of eukaryotic cells are tightly controlled by a variety of proteins in response to the cellular environment. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a receptor-interacting Ser/Thr kinase that has recently been reported as an important regulator of cell survival, apoptosis, and necroptosis; however, its role in liver cancer remains unclear. In this study, we examined the effect of siRNA-mediated RIPK1 knockdown on the survival and death of liver cancer cells. Treatment with siRIPK1 decreased the growth rate of liver cancer cells and increased apoptotic, but not necrotic cell death, which was higher in wild-type p53 (wt-p53) cells than in mutant-type p53 (mt-p53) cells. In addition, RIPK1 knockdown increased p53 expression and G1 phase arrest in wt-p53 cells. Although suppressing p53 did not alter RIPK1 expression, it did attenuate siRIPK1-induced cell death. Interestingly, RIPK1 knockdown also increased the generation of reactive oxygen species and DNA damage by inhibiting signal transduced and activator of transcription 3 (STAT3) and ATM and RAD3-related (ATR) in wt-p53 cells but not in mt-p53 cells. Moreover, STAT3 or ATR inhibition in p53 mutant cells restored siRIPK1-mediated cell death. Together, the results of this study suggest that RIPK1 suppression induces apoptotic cell death by inhibiting the STAT3/ATR axis in a p53-dependent manner. Furthermore, these findings suggest that RIPK1, alone or in combination, may be a promising target for treating liver cancer., Competing Interests: None., (AJCR Copyright © 2022.)

Cancer cells usually obtain energy from a high rate of glycolysis rather than oxidative phosphorylation under normoxia as well as hypoxia. Under these circumstances, pyruvate, the end-product of glycolysis, accumulates in cancer cells. We have previously reported that pyruvate activates endothelial cells and induces angiogenesis. Here, we examined the angiogenic activity of pyruvate in tumor cells. Plasminogen activator inhibitor-1 (PAI-1), the gene most upregulated by pyruvate, showed a pro-angiogenic activity, which was abolished by a PAI-1 neutralizing antibody. Moreover, stabilization of hypoxia-inducible factor-1α (HIF-1α) by pyruvate was required for induction of PAI-1 transcription through direct binding to hypoxia response element-2 (HRE-2) on the promoter. These results suggest that pyruvate can activate the angiogenic activity of cancer cells under normoxia and that PAI-1 may act as a pro-angiogenic factor in pyruvate-induced angiogenesis.

CuZnSOD and MnSOD have been shown to exert tumour suppressive activities; however, their exact molecular mechanism is still unclear. We investigated the molecular mechanism underlying the tumour suppressive activities of CuZnSOD and MnSOD using multicellular tumour spheroid (MTS), an in vitro tumour model. Overexpression of CuZnSOD and MnSOD significantly suppressed the growth of A549 and MCF-7 MTS, supporting a critical role(s) of reactive oxygen species (ROS) in tumour growth. In solid tumours, ROS is produced by metabolic stress due to insufficient oxygen and glucose supply and induces necrosis that is known to promote tumour progression by releasing the proinflammatory cytokine HMGB1. We observed that CuZnSOD and MnSOD overexpression prevents metabolic stress-induced necrosis and HMGB1 release by inhibiting mitochondrial ROS and intracellular O2- production in response to glucose depletion in two dimensional cell culture. CuZnSOD and MnSOD overexpression also significantly repressed the occurrence of necrosis that was observed during MTS culture. In human tumour tissues including lung pulmonary adenocarcinoma, CuZnSOD and MnSOD expression was detected in the para-necrotic region that was identified by the expression of a hypoxic marker carbonic anhydrase (CA) IX. These results suggest that CuZnSOD and MnSOD may suppress tumour growth through inhibiting metabolic stress-induced necrosis and HMGB1 release via inhibiting metabolic stress-induced mitochondrial ROS production.

Angiogenesis is important in the development and progression of cancer, therefore the therapeutic approach based on anti-angiogenesis may represent a promising therapeutic option. KR-31831 is a novel anti-ischemic agent. Previously, we reported the anti-angiogenic activity of KR-31831. In the present study we investigated the molecular mechanisms underlying anti-angiogenic activity of KR-31831. We show that KR-31831 inhibits vascular endothelial growth factor (VEGF)-induced proliferation and tube formation via release of intracellular Ca2+ and phosphorylation of extra-cellular regulated kinase 1/2 (Erk 1/2) in human umbilical vein endothelial cells (HUVECs). Moreover, the expression of VEGF receptor 2 (VEGFR2, known as Flk-1 or KDR) was reduced by the treatment of KR-31831. These results suggest that KR-31831 may have inhibitory effects on tumor angiogenesis through down-regulation of KDR expression.

The kringle domain is a triple loop structure present in angiostatin and endostatin. The disulfide bond-linked kringle architectures have been known to be essential for anti-angiogenic activity. Plasma hyaluronan binding protein (PHBP) is a novel serine protease which consists of three epidermal growth factor (EGF) domains, a kringle domain, and a serine protease domain. PHBP can be cleaved autocatalytically to generate activity and is highly expressed in the human blood and liver. To determine the anti-angiogenic activities of PHBP, we purified recombinant mouse PHBP from stable cell line overexpressing PHBP and used protein in vivo and in vitro angiogenesis assays. We found that recombinant PHBP inhibits not only angiogenesis in vivo in chorioallantoic membrane (CAM) assay but also the basic fibroblast growth factor (bFGF)-induced proliferation, invasion and tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependant manner. Moreover, we found that the kringle domain of PHBP was essential for the anti-angiogenic action of PHBP by the deletion mutants. These findings unravel a new function of PHBP as an inhibitor of the proangiogenic phenotype of vascular endothelial cells and demonstrate that the kringle domain of PHBP might be a potent novel inhibitor of activated endothelial cells in vitro and in vivo.