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Lung cancer stands as a major contributor to cancer-related fatalities globally, with cigarette smoke playing a pivotal role in its development and metastasis. Cigarette smoke is also recognized as a risk factor for bone loss disorders like osteoporosis. However, the association between cigarette smoke and another bone loss disorder, lung cancer osteolytic bone metastasis, remains largely uncertain. Our Gene Set Enrichment Analysis (GSEA) indicated that smokers among lung cancer patients exhibited higher expression levels of bone turnover gene sets. Both The Cancer Genome Atlas (TCGA) database and our clinic samples demonstrated elevated expression of the osteolytic factor IL-6 in ever-smokers with bone metastasis among lung cancer patients. Our cellular experiments revealed that benzo[α]pyrene (B[α]P) and cigarette smoke extract (CSE) promoted IL-6 production and cell migration in lung cancer. Activation of the PI3K, Akt, and NF-κB signaling pathways was involved in cigarette smoke-augmented IL-6-dependent migration. Additionally, cigarette smoke lung cancer-secreted IL-6 promoted osteoclast formation. Importantly, blocking IL-6 abolished cigarette smoke-facilitated lung cancer osteolytic bone metastasis in vivo. Our findings provide evidence that cigarette smoke is a risk factor for osteolytic bone metastasis. Thus, inhibiting IL-6 may be a valuable therapeutic strategy for managing osteolytic bone metastasis in lung cancer patients who smoke.
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Neoplasias Óseas , Movimiento Celular , Interleucina-6 , Neoplasias Pulmonares , Interleucina-6/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Humanos , Neoplasias Óseas/secundario , Neoplasias Óseas/metabolismo , Animales , Ratones , Transducción de Señal , Línea Celular Tumoral , Osteólisis/metabolismo , Humo/efectos adversos , Fumar/efectos adversosRESUMEN
Incense-burning smoke is a deleterious air pollutant that initiates cytotoxic effects by inducing apoptosis in lung epithelial cells and also acts as a risk factor for lung cancers. Auramine, an ingredient of incense smoke, has been implicated in tumor progression and cellular sensitivity in non-small cell lung cancer (NSCLC) towards anti-cancer agents through unclear mechanisms. Tumor protein p53 (TP53)-activated long intergenic non-coding RNA-p21 (lincRNA-p21) undertakes a pivotal role in regulating cell apoptosis and chemosensitivity. TP53 mutations prevalent in 50% of NSCLC, contribute to diminished therapeutic efficacy. However, the influence of auramine on chemotherapy-induced lincRNA-p21 expression and apoptosis in NSCLC with different TP53 genetic statuses remains unexplored. This study disclosed that both wild-type p53 (wtp53) and mutant p53 (mutp53) mediate lincRNA-p21 expression, albeit through distinct promoter enhancers, p53-response element (p53RE) and non-B DNA structure G-quadruplex (GQ), respectively. Intriguingly, auramine functions as an effective stabilizer of the GQ structure, augmenting mutp53-mediated lincRNA-p21 expression and enhancing apoptosis and cellular sensitivity to chemotherapy in mutp53-expressing NSCLC cells. These findings suggest a mechanism by which mutp53, in the presence of auramine, is endowed with tumor-suppressing function akin to wtp53, thereby aiding in combating chemoresistance in NSCLC cells harboring TP53 mutations.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , ARN Largo no Codificante , Proteína p53 Supresora de Tumor , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Mutación/efectos de los fármacos , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Humo/efectos adversos , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacosRESUMEN
Although many cohort studies have reported that long-term exposure to particulate matter (PM) causes lung cancer, the molecular mechanisms underlying the PM-induced increases in lung cancer progression remain unclear. We applied the lung cancer cell line A549 (Parental; A549.Par) to PM for an extended period to establish a mimic PM-exposed lung cancer cell line, A549.PM. Our results indicate that A549.PM exhibits higher cell growth and proliferation abilities compared to A549.Par cells in vitro and in vivo. The RNA sequencing analysis found amphiregulin (AREG) plays a critical role in PM-induced cell proliferation. We observed that PM increases AREG-dependent lung cancer proliferation through glutamine metabolism. In addition, the EGFR/PI3K/AKT/mTOR signaling pathway is involved in PM-induced solute carrier family A1 member 5 (SLC1A5) expression and glutamine metabolism. Our findings offer important insights into how lung cancer proliferation develops upon exposure to PM.
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Anfirregulina , Proliferación Celular , Glutamina , Neoplasias Pulmonares , Material Particulado , Anfirregulina/metabolismo , Humanos , Glutamina/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Animales , Material Particulado/efectos adversos , Células A549 , Transducción de Señal , Ratones , Línea Celular Tumoral , Serina-Treonina Quinasas TOR/metabolismo , Sistema de Transporte de Aminoácidos ASC/metabolismo , Sistema de Transporte de Aminoácidos ASC/genética , Antígenos de Histocompatibilidad MenorRESUMEN
Breast cancer stands as the predominant malignancy and primary cause of cancer-related mortality among females globally. Approximately 25% of breast cancers exhibit HER2 overexpression, imparting a more aggressive tumor phenotype and correlating with poor prognoses. Patients with metastatic breast cancer receiving HER2 tyrosine kinase inhibitors (HER2 TKIs), such as Lapatinib, develop acquired resistance within a year, posing a critical challenge in managing this disease. Here, we explore the potential of Artemisia argyi, a Chinese herbal medicine known for its anti-cancer properties, in mitigating HER2 TKI resistance in breast cancer. Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and Artemisia argyi emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer. This study not only unravels the molecular mechanisms driving cell death in HER2-positive breast cancer cells induced by Artemisia argyi but also lays the groundwork for developing novel inhibitors to enhance therapy outcomes.
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Artemisia , Neoplasias de la Mama , Resistencia a Antineoplásicos , Lapatinib , Extractos Vegetales , Receptor ErbB-2 , Serina Endopeptidasas , Lapatinib/farmacología , Lapatinib/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Artemisia/química , Femenino , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Línea Celular Tumoral , Extractos Vegetales/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Chondrosarcoma is the second most common type of bone cancer. At present, the most effective clinical course of action is surgical resection. Cisplatin is the chemotherapeutic medication most widely used for the treatment of chondrosarcoma; however, its effectiveness is severely hampered by drug resistance. In the current study, we compared cisplatin-resistant chondrosarcoma SW1353 cells with their parental cells via RNA sequencing. Our analysis revealed that glutamine metabolism is highly activated in resistant cells but glucose metabolism is not. Amphiregulin (AR), a ligand of the epidermal growth factor receptor, enhances glutamine metabolism and supports cisplatin resistance in human chondrosarcoma by promoting NADPH production and inhibiting reactive oxygen species (ROS) accumulation. The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.
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Neoplasias Óseas , Condrosarcoma , Humanos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Anfirregulina/genética , Glutamina , Resistencia a Antineoplásicos/genética , Condrosarcoma/tratamiento farmacológico , Condrosarcoma/genética , Línea Celular Tumoral , Antígenos de Histocompatibilidad Menor , Sistema de Transporte de Aminoácidos ASCRESUMEN
BACKGROUND: Artemisia argyi (A. argyi), also called Chinese mugwort, has been widely used to control pandemic diseases for thousands of years since ancient China due to its anti-microbial infection, anti-allergy, and anti-inflammation activities. Therefore, the potential of A. argyi and its constituents in reducing the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was investigated in this study. RESULTS: Among the phytochemicals in A. argyi, eriodictyol and umbelliferone were identified to target transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) proteins, the essential factors for the cellular entry of SARS-CoV-2, in both FRET-based enzymatic assays and molecular docking analyses. These two ingredients of A. argyi suppressed the infection of ACE2-expressed HEK-293 T cells with lentiviral-based pseudo-particles (Vpp) expressing wild-type and variants of SARS-CoV-2 spike (S) protein (SARS-CoV-2 S-Vpp) via interrupting the interaction between S protein and cellular receptor ACE2 and reducing the expressions of ACE2 and TMPRSS2. Oral administration with umbelliferone efficiently prevented the SARS-CoV-2 S-Vpp-induced inflammation in the lung tissues of BALB/c mice. CONCLUSIONS: Eriodictyol and umbelliferone, the phytochemicals of Artemisia argyi, potentially suppress the cellular entry of SARS-CoV-2 by preventing the protein binding activity of the S protein to ACE2.
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INTRODUCTION: Cigarette smoking is the main risk factor for lung cancer. MSCs in the TME promoting tumor angiogenesis, growth, and metastasis. SIBLING proteins enable cancer cells to extend, invade and metastasize. OBJECTIVES: Cigarette smoke promotes the progression and metastasis of lung cancer, although how this occurs is poorly understood. We evaluated the impact of whether cigarette smoking motivates SIBLING protein expression and is involved in MSC-mediated lung tumor metastasis. METHODS: We investigated the expression of OPN in the Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of lung cancer cells and tissues. The effect of OPN on the recruitment and adhesion of mesenchymal stem cells (MSCs) to lung cancer cells and lung cancers metastasis was investigated by Transwell, adhesion assays. A series of in vitro and in vivo experiments were conducted to demonstrate the mechanisms by which OPN modulates recruitment and adhesion of MSCs to lung cancer cells and lung cancer metastasis. RESULTS: Cigarette smoke extract (CSE) and benzo[α]pyrene (B[α]P) increased levels of OPN expression and facilitated the recruitment and adhesion of MSCs to lung cancer cells via JAK2/STAT3 signaling. We also observed that OPN promotes tumor-associated MSC (TA-MSC) formation through the OPN receptor (integrins αvß1, αvß3, αvß5 or CD44), inducing lung cancer cell migration and invasion. In an orthotopic mouse model of lung cancer, increases in OPN expression promoted by cigarette smoke upregulated MSC recruitment and facilitated lung cancer metastasis. Knockdown of OPN expression inhibited cigarette smoke-induced lung cancer metastasis in vivo. CONCLUSION: Cigarette smoke increases OPN expression through the JAK2/STAT3 signaling pathway to attract MSC cell recruitment and promote lung cancer metastasis. Our findings offer important insights into how lung cancer metastasis develops in smokers.
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Fumar Cigarrillos , Neoplasias Pulmonares , Células Madre Mesenquimatosas , Ratones , Animales , Osteopontina/genética , Osteopontina/metabolismo , Osteopontina/farmacología , Fumar Cigarrillos/efectos adversos , Neoplasias Pulmonares/genética , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Transducción de Señal , Nicotiana/metabolismo , Procesos NeoplásicosRESUMEN
Targeting protein kinase C (PKC) family was found to repress the migration and resistance of non-small cell lung cancer cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, none of the PKC inhibitors has been approved for anticancer therapy yet due to the limited efficacy in clinical trials, and the underlying mechanisms remain unclear. l-lactic acidosis, a common condition comprising high l-lactate concentration and acidic pH in the tumor microenvironment, has been known to induce tumor metastasis and drug resistance. In this study, l-lactic acid was found to reverse the inhibitory effects of pan-PKC inhibitors GO6983 on PKC activity, cell migration, and EGFR-TKI resistance, but these effects were not affected by the modulators of lactate receptor GPR81. Interestingly, blockade of lactate transporters, monocarboxylate transporter-1 and -4 (MCT1 and MCT4), attenuated the intracellular level of GO6983, and its inhibitory effect on PKC activity, suggesting that lactic acid promotes the resistance to PKC inhibitors by competing for the uptake through these transporters rather than by activating its receptor, GPR81. Our findings explain the underlying mechanisms of the limited response of PKC inhibitors in clinical trials.
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Acidosis Láctica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Simportadores , Receptores ErbB/metabolismo , Humanos , Ácido Láctico/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Transportadores de Ácidos Monocarboxílicos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Simportadores/metabolismo , Microambiente TumoralRESUMEN
Mutant p53 (mutp53) commonly loses its DNA binding affinity to p53 response elements (p53REs) and fails to induce apoptosis fully. However, the p53 mutation does not predict chemoresistance in all subtypes of breast cancers, and the critical determinants remain to be identified. In this study, mutp53 was found to mediate chemotherapy-induced long intergenic noncoding RNA-p21 (lincRNA-p21) expression by targeting the G-quadruplex structure rather than the p53RE on its promoter to promote chemosensitivity. However, estrogen receptor alpha (ERα) suppressed mutp53-mediated lincRNA-p21 expression by hijacking mutp53 to upregulate damaged DNA binding protein 2 (DDB2) transcription for subsequent DNA repair and chemoresistance. Levels of lincRNA-p21 positively correlated with the clinical responses of breast cancer patients to neoadjuvant chemotherapy and had an inverse correlation with the ER status and DDB2 level. In contrast, the carboplatin-induced DDB2 expression was higher in ER-positive breast tumor tissues. These results demonstrated that ER status determines the oncogenic function of mutp53 in chemoresistance by switching its target gene preference from lincRNA-p21 to DDB2 and suggest that induction of lincRNA-p21 and targeting DDB2 would be effective strategies to increase the chemosensitivity of mutp53 breast cancer patients.
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Hesperidin (HD) is a common flavanone glycoside isolated from citrus fruits and possesses great potential for cardiovascular protection. Hesperetin (HT) is an aglycone metabolite of HD with high bioavailability. Through the docking simulation, HD and HT have shown their potential to bind to two cellular proteins: transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2), which are required for the cellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results further found that HT and HD suppressed the infection of VeroE6 cells using lentiviral-based pseudo-particles with wild types and variants of SARS-CoV-2 with spike (S) proteins, by blocking the interaction between the S protein and cellular receptor ACE2 and reducing ACE2 and TMPRSS2 expression. In summary, hesperidin is a potential TMPRSS2 inhibitor for the reduction of the SARS-CoV-2 infection.
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Tratamiento Farmacológico de COVID-19 , Hesperidina/química , Hesperidina/farmacología , SARS-CoV-2/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , COVID-19/metabolismo , COVID-19/virología , Línea Celular Tumoral , Chlorocebus aethiops , Proteasas Similares a la Papaína de Coronavirus/química , Proteasas Similares a la Papaína de Coronavirus/metabolismo , Humanos , Simulación del Acoplamiento Molecular , SARS-CoV-2/metabolismo , Serina Endopeptidasas/química , Serina Endopeptidasas/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Células VeroRESUMEN
The proviral integration site for moloney murine leukemia virus 1 (Pim1) is a serine/threonine kinase and able to promote cell proliferation, survival and drug resistance. Overexpression of Pim1 has been observed in many cancer types and is associated with the poor prognosis of breast cancer. However, it remains unclear whether Pim1 kinase is a potential therapeutic target for breast cancer patients. In this study, we found that Pim1 expression was strongly associated with HER2 expression and that HER2-overexpressing breast cancer cells were more sensitive to Pim1 inhibitor-induced inhibitions of cell viability and metastatic ability. Mechanistically, Pim1 inhibitor suppressed the expression of HER2 at least in part through transcriptional level. More importantly, Pim1 inhibitor overcame the resistance of breast cancer cells to HER2 tyrosine kinase inhibitor lapatinib. In summary, downregulation of HER2 by targeting Pim1 may be a promising and effective therapeutic approach not only for anti-cancer growth but also for circumventing lapatinib resistance in HER2-positive breast cancer patients.
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The tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have been widely used for non-small cell lung cancer (NSCLC) patients, but the development of acquired resistance remains a therapeutic hurdle. The reduction of glucose uptake has been implicated in the anti-tumor activity of EGFR TKIs. In this study, the upregulation of the active sodium/glucose co-transporter 1 (SGLT1) was found to confer the development of acquired EGFR TKI resistance and was correlated with the poorer clinical outcome of the NSCLC patients who received EGFR TKI treatment. Blockade of SGLT1 overcame this resistance in vitro and in vivo by reducing glucose uptake in NSCLC cells. Mechanistically, SGLT1 protein was stabilized through the interaction with PKCδ-phosphorylated (Thr678) EGFR in the TKI-resistant cells. Our findings revealed that PKCδ/EGFR axis-dependent SGLT1 upregulation was a critical mechanism underlying the acquired resistance to EGFR TKIs. We suggest co-targeting PKCδ/SGLT1 as a potential strategy to improve the therapeutic efficacy of EGFR TKIs in NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Transportador 1 de Sodio-Glucosa , Regulación hacia ArribaRESUMEN
Transmembrane serine protease (TMPRSS2) plays an oncogenic role in prostate cancer as the fusion gene with ERG, and has also been demonstrated to be essential for the cellular entry of severe acute respiratory syndrome coronaviruses (SARS-CoV). Thus, targeting TMPRSS2 is a promising strategy for therapies against both prostate cancer and coronavirus infection. Although Nafamostat and Camostat have been identified as TMPRSS2 inhibitors, severe side effects such as cerebral hemorrhage, anaphylactoid reaction, and cardiac arrest shock greatly hamper their clinical use. Therefore, more potent and safer drugs against this serine protease should be further developed. In this study, we developed a fluorescence resonance energy transfer (FRET)-based platform for effectively screening of inhibitors against TMPRSS2 protease activity. The disruption of FRET between green and red fluorescent proteins conjugated with the substrate peptide, which corresponds to the cleavage site of SARS-CoV-2 Spike protein, was measured to determine the enzymatic activity of TMPRSS2. Through an initiate pilot screening with around 100 compounds, Flupirtine, a selective neuronal potassium channel opener, was identified as a potential TMPRSS2 inhibitor from an FDA-approved drug library by using this screening platform, and showed inhibitory effect on the TMPRSS-dependent infection of SARS-CoV-2 Spike-pseudotyped lentiviral particles. This study describes a platform proven effective for rapidly screening of TMPRSS2 inhibitors, and suggests that Flupirtine may be worthy of further consideration of repurposing to treat COVID-19 patients.
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Smoker patients with non-small cell lung cancer (NSCLC) have poorer prognosis and survival than those without smoking history. However, the mechanisms underlying the low response rate of those patients to EGFR tyrosine kinase inhibitors (TKIs) are not well understood. Here we report that exposure to cigarette smoke extract enhances glycolysis and attenuates AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR; this in turn reduces the sensitivity of NSCLC cells with wild-type EGFR (EGFRWT) to EGFR TKI by repressing expression of liver kinase B1 (LKB1), a master kinase of the AMPK subfamily, via CpG island methylation. In addition, LKB1 expression is correlated positively with sensitivity to TKI in patients with NSCLC. Moreover, combined treatment of EGFR TKI with AMPK activators synergistically increases EGFR TKI sensitivity. Collectively, the current study suggests that LKB1 may serve as a marker to predict EGFR TKI sensitivity in smokers with NSCLC carrying EGFRWT and that the combination of EGFR TKI and AMPK activator may be a potentially effective therapeutic strategy against NSCLC with EGFRWT.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/genética , Serina-Treonina Quinasas TOR/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Carcinoma de Pulmón de Células no Pequeñas/inducido químicamente , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Fumar Cigarrillos/efectos adversos , Islas de CpG/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Xenoinjertos , Humanos , Ratones , Mutación/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/genética , Transducción de Señal/efectos de los fármacos , Fumar/efectos adversosRESUMEN
Non-small cell lung cancer (NSCLC) patients with c-MET dysregulation may benefit from c-MET inhibitors therapy as inhibition of c-MET activity has emerged as a therapeutic approach against this disease. Although several c-MET inhibitors have been evaluated in multiple clinical trials in lung cancer, their benefits so far have been modest. Thus, furthering our understanding of the mechanisms contributing to the lack of success of c-MET inhibitors in clinical trials is essential toward the development of rational and effective combination strategies. Here we show that exposure of NCSLC cell lines to c-MET inhibitor tivantinib increases their expression of PD-L1, which in turn causes cells to become more resistant to T-cell killing. Mechanistically, inhibition of c-MET suppresses p-GSK3ß, leading to the stabilization of PD-L1 similar to that observed in liver cancer cells. Collectively, our findings suggest a potential crosstalk between c-MET inhibition and immune escape and provide a rationale for the combination therapy of c-MET inhibitors and immune checkpoint blockade in NSCLC.
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Cigarette smoking is one of the leading risks for lung cancer and is associated with the insensitivity of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, it remains undetermined whether and how cigarette smoke affects the therapeutic efficacy of EGFR TKIs. In this study, our data showed that chronic exposure to cigarette smoke extract (CSE) or tobacco smoke-derived carcinogen benzo[α]pyrene, B[α]P, but not nicotine-derived nitrosamine ketone (NNK), reduced the sensitivity of wild-type EGFR-expressing NSCLC cells to EGFR TKIs. Treatment with TKIs almost abolished EGFR tyrosine kinase activity but did not show an inhibitory effect on downstream Akt and ERK pathways in B[α]P-treated NSCLC cells. CSE and B[α]P transcriptionally upregulate c-MET and activate its downstream Akt pathway, which is not inhibited by EGFR TKIs. Silencing of c-MET reduces B[α]P-induced Akt activation. The CSE-treated NSCLC cells are sensitive to the c-MET inhibitor crizotinib. These findings suggest that cigarette smoke augments oncogene addiction to c-MET in NSCLC cells and that MET inhibitors may show clinical benefits for lung cancer patients with a smoking history.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Oncogenes , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/metabolismo , Fumar/efectos adversos , Benzo(a)pireno , Línea Celular Tumoral , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Modelos Biológicos , Mutación/genética , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Incense burning is common in Asian countries due to the religious beliefs. Environmental exposure to incense burning smoke is a potential risk factor for tumor development and progression of non-small cell lung cancer (NSCLC). Eastern Asia ethnic origin is strongly associated the clinical benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC patients. However, the impact of the oriental custom of incense burning on the cancer progression and the EGFR TKI-sensitivity of NSCLC remains unclear. Our results showed that long-term exposure to incense burning extract (IBE) increases the cellular proliferation with S phase accumulation and the motility activity of NSCLCs. Interestingly, IBE enhances EGFR signaling activity without affecting its genetic status, and increases the cellular sensitivity of NSCLC cell lines to EGFR TKIs. Auramine, a yellow dye for making incense sticks, was identified as a residual composition in the burning incense smoke, and showed similar EGFR TKI-sensitizing effects. Furthermore, IBE or auramine transcriptionally induce EGFR ligand amphiregulin (AREG) expression for the enhancement of EGFR activity. Neutralization of AREG reduced the viability of IBE-treated cells. These results indicated that exposure to incent smoke may enhance NSCLC progression and their sensitivity to EGFR TKIs through increasing their oncogenic addiction to AREG-induced EGFR signaling.
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Urokinase plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9) play crucial roles in tumor metastasis. Despite the well-known anticancer role of docosa-hexaenoic acid (DHA), its specific effect on ErbB2-mediated breast cancer metastasis is not fully clarified. In this study, we investigated the effect of DHA on epidermal growth factor (EGF)-induced uPA and MMP-9 activity, expression and cell invasion in SK-BR3 breast cancer cells and the possible mechanisms involved. The results showed that EGF (40 ng/ml) induced uPA and MMP-9 mRNA and protein expression, enzyme activity, and 100 µM DHA significantly inhibited EGF-induced uPA and MMP-9 mRNA, protein expression, enzyme activity, cell migration, and cell invasion. EGF increased protein expression and phosphorylation of EGF receptor (EGFR) and ErbB2 as well as of JNK2, ERK1/2, and Akt, and these changes were attenuated by DHA pretreatment. AG1478, an inhibitor of EGFR, also attenuated EGF-induced activation of EGFR, JNK2, ERK1/2, and Akt. Knocked down ErbB2 expression resulted in a similar inhibition of uPA and MMP-9 expression as noted by DHA and AG1478. Taken together, these results suggest that suppression of EGF-induced metastasis by DHA is likely through an inhibition of EGFR and ErbB2 protein expression and the downstream target uPA and MMP-9 activation in SK-BR3 human breast cancer cells.