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Tobacco smoking (TS) is implicated in lung cancer (LC) progression through the development of metabolic syndrome. However, direct evidence linking metabolic syndrome to TS-mediated LC progression remains to be established. Our findings demonstrate that 4-(methylnitrosamino)−1-(3-pyridyl)−1-butanone and benzo[a]pyrene (NNK and BaP; NB), components of tobacco smoke, induce metabolic syndrome characteristics, particularly hyperglycemia, promoting lung cancer progression in male C57BL/6 J mice. NB enhances glucose uptake in tumor-associated macrophages by increasing the expression and surface localization of glucose transporter (GLUT) 1 and 3, thereby leading to transcriptional upregulation of insulin-like growth factor 2 (IGF2), which subsequently activates insulin receptor (IR) in LC cells in a paracrine manner, promoting its nuclear import. Nuclear IR binds to nucleophosmin (NPM1), resulting in IR/NPM1-mediated activation of the CD274 promoter and expression of programmed death ligand-1 (PD-L1). Restricting glycolysis, depleting macrophages, or blocking PD-L1 inhibits NB-mediated LC progression. Analysis of patient tissues and public databases reveals elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, as well as tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/insulin receptor (pIGF-1R/IR) expression, suggesting potential poor prognostic biomarkers for LC patients. Our data indicate that paracrine IGF2/IR/NPM1/PD-L1 signaling, facilitated by NB-induced dysregulation of glucose levels and metabolic reprogramming of macrophages, contributes to TS-mediated LC progression. Tobacco smoking is an important risk factor for lung cancer. Here the authors report that tobacco carcinogens promote metabolic syndrome and metabolic reprogramming of macrophages, associated with lung cancer progression in preclinical models.

Slow-cycling/dormant cancer cells (SCCs) have pivotal roles in driving cancer relapse and drug resistance. A mechanistic explanation for cancer cell dormancy and therapeutic strategies targeting SCCs are necessary to improve patient prognosis, but are limited because of technical challenges to obtaining SCCs. Here, by applying proliferation-sensitive dyes and chemotherapeutics to non-small cell lung cancer (NSCLC) cell lines and patient-derived xenografts, we identified a distinct SCC subpopulation that resembled SCCs in patient tumors. These SCCs displayed major dormancy-like phenotypes and high survival capacity under hostile microenvironments through transcriptional upregulation of regulator of G protein signaling 2 (RGS2). Database analysis revealed RGS2 as a biomarker of retarded proliferation and poor prognosis in NSCLC. We showed that RGS2 caused prolonged translational arrest in SCCs through persistent eukaryotic initiation factor 2 (eIF2α) phosphorylation via proteasome-mediated degradation of activating transcription factor 4 (ATF4). Translational activation through RGS2 antagonism or the use of phosphodiesterase 5 inhibitors, including sildenafil (Viagra), promoted ER stress-induced apoptosis in SCCs in vitro and in vivo under stressed conditions, such as those induced by chemotherapy. Our results suggest that a low-dose chemotherapy and translation-instigating pharmacological intervention in combination is an effective strategy to prevent tumor progression in NSCLC patients after rigorous chemotherapy.

The renin-angiotensin (RA) system has been implicated in lung tumorigenesis without detailed mechanistic elucidation. Here, we demonstrate that exposure to the representative tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) promotes lung tumorigenesis through deregulation of the pulmonary RA system. Mechanistically, NNK binding to the nicotinic acetylcholine receptor (nAChR) induces Src-mediated signal transducer and activator of transcription 3 (STAT3) activation, resulting in transcriptional upregulation of angiotensinogen ( AGT ) and subsequent induction of the angiotensin II (AngII) receptor type 1 (AGTR1) signaling pathway. In parallel, NNK concurrently increases insulin-like growth factor 2 (IGF2) production and activation of IGF-1R/insulin receptor (IR) signaling via a two-step pathway involving transcriptional upregulation of IGF2 through STAT3 activation and enhanced secretion from intracellular storage through AngII/AGTR1/PLC-intervened calcium release. NNK-mediated crosstalk between IGF-1R/IR and AGTR1 signaling promoted tumorigenic activity in lung epithelial and stromal cells. Lung tumorigenesis caused by NNK exposure or alveolar type 2 cell-specific Src activation was suppressed by heterozygous Agt knockout or clinically available inhibitors of the nAChR/Src or AngII/AGTR1 pathways. These results demonstrate that NNK-induced stimulation of the lung RA system leads to IGF2-mediated IGF-1R/IR signaling activation in lung epithelial and stromal cells, resulting in lung tumorigenesis in smokers. Lung cancer: an opportunity to repurpose available drugs A cellular signaling pathway primarily known for modulating blood pressure also drives the progression of lung cancers arising from tobacco use. Dysfunction in the renin-angiotensin system can lead to hypertension, and many patients are treated with drugs targeting this signaling pathway. The renin-angiotensin system is also involved in certain cancers, and researchers led by Ho-Young Lee at Seoul National University, South Korea, have shown how a tobacco-derived carcinogen called NNK promotes lung cancer via this pathway. Working with cultured cells and animal models, the researchers showed that NNK stimulates production of angiotensin in respiratory tissues, resulting in IGF2 secretion. The IGF-1R signaling activation ultimately leads to transformation of pulmonary epithelial cells into cancerous ones. Antihypertensive drugs that act on the renin-angiotensin pathway suppressed NNK-mediated tumorigenesis in mice, highlighting the possibility of preventing lung cancer with existing drugs.

Wounds are injuries to skin that frequently occur in daily life. Delayed wound healing can affect quality of life. Therefore, new materials for treating skin wounds are continuously being developed. Lava seawater is a groundwater resource in the Jeju region of the Republic of Korea with high mineral content, making it popular in industrial applications such as cosmetics. Our study investigated the effect and mechanism of action of lava seawater, desalinated using electrodialysis, on wound healing. HaCaT cells were cultured in media containing different concentrations of desalinated lava seawater, and scratch wound and Transwell migration assays were performed to assess wound-healing performance. The expression of matrix metalloproteinase-9 (MMP9) and extracellular signal-regulated kinase (ERK) was studied using western blotting. We confirmed that the wound-healing effect of desalinated lava seawater was because of the migration of keratinocytes. Additionally, desalinated lava seawater increased the mRNA expression of vascular endothelial growth factor, platelet-derived growth factor, and angiopoietin-1, which are associated with angiogenesis. Desalinated lava seawater also promoted wound healing by inducing the expression of MMP9, which facilitated keratinocyte migration by loosening the contact between keratinocytes and the matrix. In addition, ERK was activated by desalinated lava seawater, and the expression of MMP9 was promoted, inducing migration of HaCaT cells and increasing wound closure. This study provides insights into the potential impact of desalinated lava seawater produced from lava seawater on wound healing, its underlying mechanism of action, and potential applications.

Regulatory T cells (Tregs) play a crucial role in inflammatory responses by regulating the activity of various immune cells. M2 macrophages induced by IL-10 and TGF-β exhibit anti-inflammatory functions and induce Treg differentiation. Although the beneficial effects of 3-bromo-4,5-dihydroxybenzaldehyde (BDB) on various diseases have been widely reported, the mechanisms, through which it alleviates allergic contact dermatitis (ACD) via Tregs and macrophages, are not well understood. Therefore, this study aimed to explore whether BDB suppresses ACD and induces Treg generation. Mice were sensitized with 1% dinitrochlorobenzene (DNCB), followed by the application of 0.3% DNCB to their ears every 3 days for 31 days. BDB (100 mg/kg) was administered orally once daily throughout the 31 days. Cytokine and transcription factor expression were analyzed via real-time PCR and western blotting, while CD4 Foxp3 T cell differentiation and T cell proliferation were evaluated using flow cytometry. BDB exhibited therapeutic efficacy in mice with ACD. In this study, the administration of BDB promoted the upregulation of transforming growth factor beta (TGF-β)-dependent CD4 Foxp3 T cells. BDB elicited T cell hypo-responsiveness and suppressed the expression of cytokines related to the Th1, Th2, and Th17 cell subsets. BDB-M2 macrophages directly mediated the differentiation of CD4 Foxp3 T cells from CD4 T cells and concurrently suppressed the proliferation of CD4 T cells. BDB augments M2 macrophage function and induction of Tregs confers effective protection against ACD in mice. Consequently, BDB may represent a promising therapeutic approach for the treatment of inflammatory skin diseases.

Background Cancer stem-like cells (CSCs) play a pivotal role in lung tumor formation and progression. Nerve injury-induced protein 1 (Ninjurin1, Ninj1) has been implicated in lung cancer; however, the pathological role of Ninj1 in the context of lung tumorigenesis remains largely unknown. Methods The role of Ninj1 in the survival of non-small cell lung cancer (NSCLC) CSCs within microenvironments exhibiting hazardous conditions was assessed by utilizing patient tissues and transgenic mouse models where Ninj1 repression and oncogenic Kras G12D/+ or carcinogen-induced genetic changes were induced in putative pulmonary stem cells (SCs). Additionally, NSCLC cell lines and primary cultures of patient-derived tumors, particularly Ninj1 high and Ninj1 low subpopulations and those with gain- or loss-of- Ninj1 expression, and also publicly available data were all used to assess the role of Ninj1 in lung tumorigenesis. Results Ninj1 expression is elevated in various human NSCLC cell lines and tumors, and elevated expression of this protein can serve as a biomarker for poor prognosis in patients with NSCLC. Elevated Ninj1 expression in pulmonary SCs with oncogenic changes promotes lung tumor growth in mice. Ninj1 high subpopulations within NSCLC cell lines, patient-derived tumors, and NSCLC cells with gain-of- Ninj1 expression exhibited CSC-associated phenotypes and significantly enhanced survival capacities in vitro and in vivo in the presence of various cell death inducers. Mechanistically, Ninj1 forms an assembly with lipoprotein receptor-related protein 6 (LRP6) through its extracellular N-terminal domain and recruits Frizzled2 (FZD2) and various downstream signaling mediators, ultimately resulting in transcriptional upregulation of target genes of the LRP6/β-catenin signaling pathway. Conclusions Ninj1 may act as a driver of lung tumor formation and progression by protecting NSCLC CSCs from hostile microenvironments through ligand-independent activation of LRP6/β-catenin signaling.

Fucoidan, a sulfated polysaccharide, has a variety of biological activities, such as anti-cancer, anti-angiogenic and anti-inflammatory. However, the mechanisms of action of fucoidan as an anti-cancer agent have not been fully elucidated. The present study examined the anti-cancer effect of fucoidan obtained from Undaria pinnatifida in PC-3 cells, human prostate cancer cells. Fucoidan induced the apoptosis of PC-3 cells by activating both intrinsic and extrinsic pathways. The induction of apoptosis was accompanied by the activation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK1/2 MAPK) and the inactivation of p38 MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt. In addition, fucoidan also induced the up-regulation of p21Cip1/Waf and down-regulation of E2F-1 cell-cycle-related proteins. Furthermore, in the Wnt/β-catenin pathway, fucoidan activated GSK-3β that resulted in the decrease of β-catenin level, followed by the decrease of c-myc and cyclin D1 expressions, target genes of β-catenin in PC-3 cells. These results suggested that fucoidan treatment could induce intrinsic and extrinsic apoptosis pathways via the activation of ERK1/2 MAPK, the inactivation of p38 MAPK and PI3K/Akt signaling pathway, and the down-regulation of Wnt/β-catenin signaling pathway in PC-3 prostate cancer cells. These data support that fucoidan might have potential for the treatment of prostate cancer.

Despite the development of advanced therapeutic regimens such as molecular targeted therapy and immunotherapy, the 5-year survival of patients with lung cancer is still less than 20%, suggesting the need to develop additional treatment strategies. The molecular chaperone heat shock protein 90 (Hsp90) plays important roles in the maturation of oncogenic proteins and thus has been considered as an anticancer therapeutic target. Here we show the efficacy and biological mechanism of a Hsp90 inhibitor NCT-50, a novobiocin-deguelin analog hybridizing the pharmacophores of these known Hsp90 inhibitors. NCT-50 exhibited significant inhibitory effects on the viability and colony formation of non-small cell lung cancer (NSCLC) cells and those carrying resistance to chemotherapy. In contrast, NCT-50 showed minimal effects on the viability of normal cells. NCT-50 induced apoptosis in NSCLC cells, inhibited the expression and activity of several Hsp90 clients including hypoxia-inducible factor (HIF)-1α, and suppressed pro-angiogenic effects of NSCLC cells. Further biochemical and in silico studies revealed that NCT-50 downregulated Hsp90 function by interacting with the C-terminal ATP-binding pocket of Hsp90, leading to decrease in the interaction with Hsp90 client proteins. These results suggest the potential of NCT-50 as an anticancer Hsp90 inhibitor.

Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics.