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1.
Sci Rep ; 12(1): 6367, 2022 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-35430596

RESUMO

The identification of acquired resistance mutations has been essential in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) active mutations. Rebiopsy plays a pivotal role in selecting the optimal treatment for patients who develop resistance to initial EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This multicenter, observational study was conducted to investigate the details of rebiopsy in Japanese clinical practice. The primary endpoints were the implementation rate of rebiopsy and the concordance rate for T790M mutation detection between histological and cytological specimens using the cobas EGFR Mutation Test, version 2. One hundred ninety-four patients with EGFR-mutant NSCLC were enrolled, and 120 patients developed acquired resistance to EGFR-TKIs. The median age was 68 years (range 20-87), and 52.5% of the patients were women. Rebiopsy was performed in 109 patients, and the implementation rate of rebiopsy was 90.8%. The success rates of rebiopsy in the total, histology, cytology and liquid biopsy populations were 67.9%, 81.3%, 66.7% and 43.8%, respectively. The positive percent agreement and the negative percent agreement in the detection of the T790M mutation between the histological and cytological specimens were both 90.9%. Obtaining histological or cytological tissue samples at rebiopsy may contribute to improving the detection rate of the T790M mutation (trial registration number: UMIN000026019).


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Adulto Jovem
2.
Aging (Albany NY) ; 14(3): 1068-1086, 2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-35158337

RESUMO

Radiation therapy is a commonly used treatment modality for cancer. Although effective in providing local tumor control, radiation causes oxidative stress, inflammation, immunomodulatory and mitogenic cytokine production, extracellular matrix production, and premature senescence in lung parenchyma. The senescence associated secretory phenotype (SASP) can promote inflammation and stimulate alterations in the surrounding tissue. Therefore, we hypothesized that radiation-induced senescent parenchymal cells in irradiated lung would enhance tumor growth. Using a murine syngeneic tumor model of melanoma and non-small cell lung cancer lung metastasis, we demonstrate that radiation causes a significant increase in markers of premature senescence in lung parenchyma within 4 to 8 weeks. Further, injection of B16F0 (melanoma) or Lewis Lung carcinoma (epidermoid lung cancer) cells at these time points after radiation results in an increase in the number and size of pulmonary tumor nodules relative to unirradiated mice. Treatment of irradiated mice with a senolytic agent (ABT-737) or agents that prevent senescence (rapamycin, INK-128) was sufficient to reduce radiation-induced lung parenchymal senescence and to mitigate radiation-enhanced tumor growth. These agents abrogated radiation-induced expression of 12-Lipoxygenase (12-LOX), a molecule implicated in several deleterious effects of senescence. Deficiency of 12-LOX prevented radiation-enhanced tumor growth. Together, these data demonstrate the pro-tumorigenic role of radiation-induced senescence, introduces the dual TORC inhibitor INK-128 as an effective agent for prevention of radiation-induced normal tissue senescence, and identifies senescence-associated 12-LOX activity as an important component of the pro-tumorigenic irradiated tissue microenvironment. These studies suggest that combining senotherapeutic agents with radiotherapy may decrease post-therapy tumor growth.


Assuntos
Carcinoma Pulmonar de Lewis , Neoplasias Pulmonares , Melanoma Experimental , Animais , Araquidonato 12-Lipoxigenase/farmacologia , Carcinoma Pulmonar de Lewis/enzimologia , Carcinoma Pulmonar de Lewis/patologia , Processos de Crescimento Celular , Senescência Celular , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Melanoma Experimental/enzimologia , Melanoma Experimental/patologia , Camundongos , Microambiente Tumoral
3.
Int J Mol Sci ; 23(3)2022 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-35163585

RESUMO

BACKGROUND: The treatment of non-small-cell lung cancer (NSCLC) involves platinum-based chemotherapy. It is typically accompanied by chemoresistance resulting from antioxidant properties conferred by cancer stem cells (CSCs). Human epidermal growth factor receptor 2 (HER2) enhances CSCs and antioxidant properties in cancers, including NSCLC. METHODS: Here, we elucidated the role of histamine N-methyltransferase (HNMT), a histamine metabolism enzyme significantly upregulated in NSCLC and coexpressed with HER2. HNMT expression in lung cancer tissues was determined using quantitative reverse transcription PCR (RT-qPCR). A publicly available dataset was used to determine HNMT's potential as an NSCLC target molecule. Immunohistochemistry and coimmunoprecipitation were used to determine HNMT-HER2 correlations and interactions, respectively. HNMT shRNA and overexpression plasmids were used to explore HNMT functions in vitro and in vivo. We also examined miRNAs that may target HNMT and investigated HNMT/HER2's role on NSCLC cells' antioxidant properties. Finally, how HNMT loss affects NSCLC cells' sensitivity to cisplatin was investigated. RESULTS: HNMT was significantly upregulated in human NSCLC tissues, conferred a worse prognosis, and was coexpressed with HER2. HNMT depletion and overexpression respectively decreased and increased cell proliferation, colony formation, tumorsphere formation, and CSCs marker expression. Coimmunoprecipitation analysis indicated that HNMT directly interacts with HER2. TARGETSCAN analysis revealed that HNMT is a miR-223 and miR-3065-5p target. TBHp treatment increased HER2 expression, whereas shHNMT disrupted the Nuclear factor erythroid 2-related factor 2 (Nrf2)/ hemeoxygenase-1 (HO-1)/HER2 axis and increased reactive oxygen species accumulation in NSCLC cells. Finally, shHNMT sensitized H441 cells to cisplatin treatment in vitro and in vivo. CONCLUSIONS: Therefore, HNMT upregulation in NSCLC cells may upregulate HER2 expression, increasing tumorigenicity and chemoresistance through CSCs maintenance and antioxidant properties. This newly discovered regulatory axis may aid in retarding NSCLC progression and chemoresistance.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histamina N-Metiltransferase/biossíntese , Neoplasias Pulmonares/enzimologia , Células-Tronco Neoplásicas/enzimologia , Estresse Oxidativo , Receptor ErbB-2/metabolismo , Regulação para Cima , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Histamina N-Metiltransferase/genética , Humanos , Neoplasias Pulmonares/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptor ErbB-2/genética
4.
Mol Cancer ; 21(1): 43, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35144642

RESUMO

BACKGROUND: Identification of potential novel targets for reversing resistance to Epidermal Growth Factor Receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) holds great promise for the treatment of relapsed lung adenocarcinoma (LUAD). In the present study, we aim to investigate the role of methyltransferase-like 7B (METTL7B) in inducing EGFR-TKIs resistance in LUAD and whether it could be a therapeutic target for reversing the resistance. METHODS: METTL7B-overexpressed LUAD cell lines, gefitinib and osimertinib-resistant Cell-Derived tumor Xenograft (CDX) and Patient-Derived tumor Xenograft (PDX) mouse models were employed to evaluate the role of METTL7B in TKIs resistance. Ultraperformance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was used to identify the metabolites regulated by METTL7B. Methylated RNA immunoprecipitation (MeRIP)-qPCR analysis was performed to measure the N6-methyladenosine (m6A) status of mRNA of METTL7B targeted genes. Gold nanocluster-assisted delivery of siRNA targeting METTL7B (GNC-siMETTL7B) was applied to evaluate the effect of METTL7B in TKIs resistance. RESULTS: Increased expression of METTL7B was found in TKIs-resistant LUAD cells and overexpression of METTL7B in LUAD cells induced TKIs resistance both in vitro and in vivo. Activated ROS-metabolism was identified in METTL7B-overexpressed LUAD cells, accompanied with upregulated protein level of GPX4, HMOX1 and SOD1 and their enzymatic activities. Globally elevated m6A levels were found in METTL7B-overexpressed LUAD cells, which was reduced by knock-down of METTL7B. METTL7B induced m6A modification of GPX4, HMOX1 and SOD1 mRNA. Knock-down of METTL7B by siRNA re-sensitized LUAD cells to gefitinib and osimertinib both in vitro and in vivo. CONCLUSIONS: This study uncovered a new critical link in METTL7B, glutathione metabolism and drug resistance. Our findings demonstrated that METTL7B inhibitors could be used for reversing TKIs resistance in LUAD patients.


Assuntos
Adenocarcinoma de Pulmão , Proteínas de Transporte , Receptores ErbB , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Cromatografia Líquida , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Espectrometria de Massas em Tandem , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Anticancer Res ; 42(3): 1221-1227, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35220212

RESUMO

BACKGROUND/AIM: γ-Glutamyl cyclotransferase (GGCT) is up-regulated in various cancer types, including lung cancer. In this study, we evaluated efficacy of gapmer-type antisense oligonucleotides (ASOs) targeting GGCT in an A549 lung cancer xenograft mouse model and studied their mechanisms of action. MATERIALS AND METHODS: GGCT was inhibited using GGCT-ASOs and cell proliferation was evaluated by dye exclusion test. Western blot analysis was conducted to measure expression of GGCT, p21, p16 and p27, phosphorylation of AMP-activated protein kinase, and caspase activation in A549 cells. Induction of apoptosis and up-regulation of reactive oxygen species were assessed by flow cytometry using annexin V staining and 2',7'-dichlorodihydrofluorescein diacetate dye, respectively. RESULTS: GGCT-ASOs suppressed GGCT expression in A549 cells, inhibited proliferation, and induced apoptosis with activation of caspases. GGCT-ASOs also increased expression of cell-cycle regulating proteins, phospho-AMPK and ROS levels. Systemic administration of GGCT-ASOs to animals bearing A549 lung cancer xenografts showed significant antitumor effects without evident toxicity. CONCLUSION: GGCT-ASOs appear to be promising as novel cancer therapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Oligonucleotídeos Antissenso/farmacologia , gama-Glutamilciclotransferase/metabolismo , Células A549 , Animais , Apoptose , Caspases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cicloeximida/análogos & derivados , Cicloeximida/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos SCID , Transdução de Sinais , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , gama-Glutamilciclotransferase/genética
6.
Signal Transduct Target Ther ; 7(1): 25, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35087031

RESUMO

WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient. MTD was not reached. Overall, 140 of the 152 (92%) patients experienced treatment-related adverse events (TRAEs) and 35 of the 152 (23%) patients had TRAEs ≥grade 3. The overall ORR was 59.3% (32 of 54) for the dose-escalation phase and 56.6% (56 of 99) for the dose-expansion phase. For patients who were ALK-rearranged and ALK TKI naive, the ORR were 81.0% (17 of 21) in the dose-escalation phase and 76.3% (29 of 38) in the dose-expansion phase, and for patients who previously received crizotinib as the only ALK TKI, the ORR were 38.1% (8 of 21) and 45.7% (21 of 46) for the two phases, respectively. For patients who were ROS1-rearranged, the ORR were 30.0% (3 of 10) in the dose-escalation phase and 44.4% (4 of 9) in the dose-expansion phase. WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.


Assuntos
Quinase do Linfoma Anaplásico/genética , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas , Rearranjo Gênico , Neoplasias Pulmonares , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos
7.
J Clin Invest ; 132(4)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34990404

RESUMO

BACKGROUNDThe KRAS proto-oncogene is among the most frequently mutated genes in cancer, yet for 40 years it remained an elusive therapeutic target. Recently, allosteric inhibitors that covalently bind to KRAS G12C mutations have been approved for use in lung adenocarcinomas. Although responses are observed, they are often short-lived, thus making in-depth characterization of the mechanisms of resistance of paramount importance.METHODSHere, we present a rapid-autopsy case of a patient who had a KRASG12C-mutant lung adenocarcinoma who initially responded to a KRAS G12C inhibitor but then rapidly developed resistance. Using deep-RNA and whole-exome sequencing comparing pretreatment, posttreatment, and matched normal tissues, we uncover numerous mechanisms of resistance to direct KRAS inhibition.RESULTSIn addition to decreased KRAS G12C-mutant allele frequency in refractory tumors, we also found reactivation of the MAPK pathway despite no new mutations in KRAS or its downstream mediators. Tumor cell-intrinsic and non-cell autonomous mechanisms included increased complement activation, coagulation, and tumor angiogenesis, and several lines of evidence of immunologic evasion.CONCLUSIONTogether, our findings reveal numerous mechanisms of resistance to current KRAS G12C inhibitors through enrichment of clonal populations, KRAS-independent downstream signaling, and diverse remodeling of the tumor microenvironment.FUNDINGRichard and Fran Duley, Jimmy and Kay Mann, the NIH, and the North Carolina Biotechnology Center.


Assuntos
Adenocarcinoma de Pulmão , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais/genética , Microambiente Tumoral/genética , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/genética , Substituição de Aminoácidos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
8.
Eur J Clin Pharmacol ; 78(4): 613-621, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35039908

RESUMO

PURPOSE: Aprepitant is used with dexamethasone and 5-HT3 receptor antagonists as an antiemetic treatment for chemotherapy, including cisplatin. Aprepitant is a substrate of cytochrome P450 (CYP) 3A4 and is known to cause its inhibition and induction. In addition, dexamethasone is a CYP3A4 substrate that induces CYP3A4 and CYP3A5 expression. In this study, we aimed to quantitatively evaluate the profile of CYP3A activity using its endogenous markers in non-small cell lung cancer patients receiving a standard cisplatin regimen with antiemetics, including aprepitant. METHODS: Urinary 11ß-hydroxytestosterone (11ß-OHT)/testosterone concentration ratio and plasma 4ß-hydroxycholesterol (4ß-OHC) concentrations were measured before and after cisplatin treatment (days 1, 4, and 8). CYP3A5 was genotyped, and plasma aprepitant concentrations were measured on day 4 to examine its influence on CYP3A endogenous markers. RESULTS: The urinary 11ß-OHT/testosterone concentration ratio in the 35 patients included in this study increased by 2.65-fold and 1.21-fold on days 4 and 8 compared with day 1, respectively. Their plasma 4ß-OHC concentration increased by 1.46-fold and 1.66-fold, respectively. The mean plasma aprepitant concentration on day 4 was 1,451 ng/mL, which is far lower than its inhibitory constant. The allele frequencies of CYP3A5*1 and CYP3A5*3 were 0.229 and 0.771, respectively. In patients with the CYP3A5*1 allele, the plasma 4ß-OHC concentration was significantly lower at baseline but more potently increased with chemotherapy. CONCLUSION: CYP3A activity was significantly induced from day 4 to day 8 in patients receiving cisplatin and three antiemetic drugs.


Assuntos
Antieméticos , Aprepitanto , Carcinoma Pulmonar de Células não Pequenas , Cisplatino , Citocromo P-450 CYP3A , Dexametasona , Neoplasias Pulmonares , Antieméticos/uso terapêutico , Aprepitanto/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Dexametasona/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Vômito/induzido quimicamente , Vômito/prevenção & controle
9.
J Cell Biochem ; 123(2): 359-374, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34751461

RESUMO

Identifying novel molecules as potential kinase inhibitors are gaining significant attention globally. The present study suggests Myricetin as a potential inhibitor of microtubule-affinity regulating kinase (MARK4), adding another molecule to the existing list of anticancer therapeutics. MARK4 regulates initial cell division steps and is a potent druggable target for various cancers. Structure-based docking with 100 ns molecular dynamics simulation depicted activity of Myricetin in the active site pocket of MARK4 and the formation of a stable complex. The fluorescence-based assay showed excellent affinity of Myricetin to MARK4 guided by static and dynamic quenching. Moreover, the assessment of enthalpy change (∆H) and entropy change (∆S) delineated electrostatic interactions as a dominant force in the MARK4-myricetin interaction. Isothermal titration calorimetric measurements revealed spontaneous binding of Myricetin with MARK4. Further, the kinase assay depicted significant inhibition of MARK4 by Myricetin with IC50 = 3.11 µM. Additionally, cell proliferation studies established that Myricetin significantly inhibited the cancer cells (MCF-7 and A549) proliferation, and inducing apoptosis. This study provides a solid rationale for developing Myricetin as a promising anticancer molecule in the MARK4 mediated malignancies.


Assuntos
Neoplasias da Mama , Flavonoides , Neoplasias Pulmonares , Proteínas de Neoplasias , Células A549 , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Feminino , Flavonoides/química , Flavonoides/farmacologia , Células HEK293 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Células MCF-7 , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , /química , /metabolismo
11.
Cells ; 10(12)2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34943871

RESUMO

FGFR signalling is one of the most prominent pathways involved in cell growth and development as well as cancer progression. FGFR1 amplification occurs in approximately 20% of all squamous cell lung carcinomas (SCC), a predominant subtype of non-small cell lung carcinoma (NSCLC), indicating FGFR as a potential target for the new anti-cancer treatment. However, acquired resistance to this type of therapies remains a serious clinical challenge. Here, we investigated the NSCLC cell lines response and potential mechanism of acquired resistance to novel selective FGFR inhibitor CPL304110. We found that despite significant genomic differences between CPL304110-sensitive cell lines, their resistant variants were characterised by upregulated p38 expression/phosphorylation, as well as enhanced expression of genes involved in MAPK signalling. We revealed that p38 inhibition restored sensitivity to CPL304110 in these cells. Moreover, the overexpression of this kinase in parental cells led to impaired response to FGFR inhibition, thus confirming that p38 MAPK is a driver of resistance to a novel FGFR inhibitor. Taken together, our results provide an insight into the potential direction for NSCLC targeted therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Biomarcadores Tumorais/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo
12.
Cell Rep ; 37(12): 110137, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34936872

RESUMO

Glycolytic reprogramming is a typical feature of cancer. However, the cancer-specific modulation of glycolytic enzymes requires systematic elucidation. Here, we report a range of dysregulated modifications in association with a family of enzymes specifically related to the glycolysis pathway by systematic identification of delta masses at the proteomic scale in human non-small-cell lung cancer. The most significant modification is the delta mass of 79.967 Da at serine 58 (Ser58) of triosephosphate isomerase (TPI), which is confirmed to be phosphorylation. Blocking TPI Ser58 phosphorylation dramatically inhibits glycolysis, cancer growth, and metastasis. The protein kinase PRKACA directly phosphorylates TPI Ser58, thereby enhancing TPI enzymatic activity and glycolysis. The upregulation of TPI Ser58 phosphorylation is detected in various human tumor specimens and correlates with poor survival. Therefore, our study identifies a number of cancer-specific protein modifications spanned on glycolytic enzymes and unravels the significance of TPI Ser58 phosphorylation in glycolysis and lung cancer development.


Assuntos
Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Glicólise , Neoplasias Pulmonares/metabolismo , Processamento de Proteína Pós-Traducional , Proteoma/metabolismo , Triose-Fosfato Isomerase/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação , Proteômica
13.
Int J Mol Sci ; 22(22)2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34830123

RESUMO

New drugs, including immune checkpoint inhibitors and targeted therapy, have changed the prognosis in a subset of patients with advanced lung cancer, and are now actively investigated in a number of trials with neoadjuvant and adjuvant regimens. However, no phase III randomized studies were published yet. The current narrative review proves that targeted therapies are safe in neoadjuvant approach. Unsurprisingly, administration of therapy is related to an acceptable toxicity profile. Severe adverse events' rate that rarely compromises outcomes of patients with advanced lung cancer is not that commonly accepted in early lung cancer as it may lead to missing the chance of curative surgery. Among those complications, the most important factors that may limit the use of targeted therapies are severe respiratory adverse events precluding the resection occurring after treatment with some anaplastic lymphoma kinase and rarely after epidermal growth factor receptor tyrosine kinase inhibitors. At this point, in the presented literature assessing the feasibility of neoadjuvant therapies with anaplastic lymphoma kinase and epidermal growth factor receptor tyrosine kinase inhibitors, we did not find any unexpected intraoperative events that would be of special interest to a thoracic surgeon. Moreover, the postoperative course was associated with typical rate of complications.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Quinase do Linfoma Anaplásico/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Diarreia/induzido quimicamente , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/cirurgia , Náusea/induzido quimicamente , Terapia Neoadjuvante/métodos , Inibidores de Proteínas Quinases/efeitos adversos
14.
Int J Mol Sci ; 22(22)2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34830188

RESUMO

Cytochrome P450 2A13 is an omitted brother of CYP2A6 that has an important role in the drug metabolism of liver. Due to extrahepatic expression, it has gained less attention than CYP2A6, despite the fact that it plays a significant role in toxicant-induced pulmonary lesions and, therefore, lung cancer. The purpose of this mini-review is to summarize the basic knowledge about this enzyme in relation to the substrates, inhibitors, genetic polymorphisms, and transcriptional regulation that are known so far (September 2021).


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Pulmão/metabolismo , Polimorfismo Genético , Animais , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Hidrocarboneto de Aril Hidroxilases/metabolismo , Humanos , Pulmão/enzimologia , Pulmão/patologia , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Metoxaleno/farmacologia , Especificidade por Substrato
15.
Cells ; 10(11)2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34831355

RESUMO

The STK11/LKB1 gene codes for liver kinase B1 (STK11/LKB1), a highly conserved serine/threonine kinase involved in many energy-related cellular processes. The canonical tumor-suppressive role for STK11/LKB1 involves the activation of AMPK-related kinases, a master regulator of cell survival during stress conditions. In pre-clinical models, inactivation of STK11/LKB1 leads to the progression of lung cancer with the acquisition of metastatic properties. Moreover, preclinical and clinical data have shown that inactivation of STK11/LKB1 is associated with an inert tumor immune microenvironment, with a reduced density of infiltrating cytotoxic CD8+ T lymphocytes, a lower expression of PD-(L)1, and a neutrophil-enriched tumor microenvironment. In this review, we first describe the biological function of STK11/LKB1 and the role of its inactivation in cancer cells. We report descriptive epidemiology, co-occurring genomic alterations, and prognostic impact for lung cancer patients. Finally, we discuss recent data based on pre-clinical models and lung cancer cohorts analyzing the results of STK11/LKB1 alterations on the immune system and response or resistance to immune checkpoint inhibitors.


Assuntos
Imunidade , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/imunologia , /metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Prognóstico , Proteínas Supressoras de Tumor/metabolismo
16.
Bioengineered ; 12(2): 12227-12235, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34783291

RESUMO

Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell lung cancer with poor prognosis. This study aimed to explore the role of KDM2B in the development of LUSC. The results of this study demonstrated that KDM2B was upregulated in LUSC tissues and cell lines. Knockdown of KDM2B reduced cell viability and colony forming ability in SK-MES-1 and NCI-H520 cells. KDM2B inhibition reduced glucose consumption, lactate production, ATP level, and also downregulated the expression of LDHA and GLUT1. KDM2B knockdown decreased the protein expression of LC3-I and p62, and increased LC3-II and Beclin-1. Furthermore, KDM2B silencing inhibited the phosphorylation of AKT, mTOR and P70S6K. KDM2B knockdown led to reduced tumor size in mouse model. In conclusion, KDM2B is upregulated in LUSC tissues and cell lines. KDM2B silencing inhibits glycolysis and promotes autophagy through inactivation of the PI3K/Akt/mTOR signaling pathway.


Assuntos
Autofagia , Carcinoma de Células Escamosas/enzimologia , Proteínas F-Box/metabolismo , Glicólise , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias Pulmonares/enzimologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Autofagia/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas F-Box/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glicólise/genética , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Transdução de Sinais , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cell Rep ; 37(5): 109905, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34731623

RESUMO

Despite the undisputable role of the small GTPase Rac1 in the regulation of actin cytoskeleton reorganization, the Rac guanine-nucleotide exchange factors (Rac-GEFs) involved in Rac1-mediated motility and invasion in human lung adenocarcinoma cells remain largely unknown. Here, we identify FARP1, ARHGEF39, and TIAM2 as essential Rac-GEFs responsible for Rac1-mediated lung cancer cell migration upon EGFR and c-Met activation. Noteworthily, these Rac-GEFs operate in a non-redundant manner by controlling distinctive aspects of ruffle dynamics formation. Mechanistic analysis reveals a leading role of the AXL-Gab1-PI3K axis in conferring pro-motility traits downstream of EGFR. Along with the positive association between the overexpression of Rac-GEFs and poor lung adenocarcinoma patient survival, we show that FARP1 and ARHGEF39 are upregulated in EpCam+ cells sorted from primary human lung adenocarcinomas. Overall, our study reveals fundamental insights into the complex intricacies underlying Rac-GEF-mediated cancer cell motility signaling, hence underscoring promising targets for metastatic lung cancer therapy.


Assuntos
Adenocarcinoma de Pulmão/enzimologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Neoplasias Pulmonares/enzimologia , Receptores Proteína Tirosina Quinases/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Movimento Celular , Molécula de Adesão da Célula Epitelial/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP/genética
18.
Anticancer Res ; 41(11): 5481-5488, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34732418

RESUMO

BACKGROUND/AIM: Aldehyde dehydrogenases (ALDHs) are considered as markers for normal and cancer stem cells (CSC) and are involved in cell metabolism, proliferation, differentiation, stemness, and retinoic acid (RA) biosynthesis. The aim of the present study was to identify the ALDH isoforms that are associated with the CSC phenotype in non-small cell lung and hepatocellular carcinomas. MATERIALS AND METHODS: We utilized lung (A549) and hepatocellular (HepG2) cancer cells and generated tumor spheres to isolate the CSC sub-population. RESULTS: The CSC enrichment was confirmed by the up-regulation of various CSC-related genes. Comparative qPCR analysis indicated the up-regulation of several ALDH isoforms in A549 and HepG2 spheres. Interestingly, cyclin D1 and Akt, down-stream targets of the RA signaling pathway, were also shown to be significantly up-regulated in both sphere populations. CONCLUSION: Specific ALDH isoforms appear to be important mediators for the acquisition of an CSC phenotype and thus, are potential promising targets for CSC-based therapeutic approaches in lung and hepatocellular carcinomas.


Assuntos
Aldeído Desidrogenase/metabolismo , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Neoplasias Pulmonares/enzimologia , Células-Tronco Neoplásicas/enzimologia , Células A549 , Aldeído Desidrogenase/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Isoenzimas , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/patologia , Fenótipo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Esferoides Celulares
19.
Thorac Cancer ; 12(23): 3184-3193, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34729938

RESUMO

BACKGROUND: Activation of ALK leads to a high level of aerobic glycolysis related to crizotinib insensitivity in anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK+ NSCLC). The strategy and mechanism of glycolysis inhibition in sensitizing ALK+ NSCLC cells to crizotinib requires further investigation. METHODS: The levels of glycolysis in H3122 and H2228 cells were evaluated through detection of glucose consumption and lactate production. MTT assay was used to explore the effects of glycolytic inhibitors on crizotinib sensitivity, and the potential mechanism of action were detected by colony formation, Ki67 incorporation assay, transwell assay, small interfering RNA technology and western blot analysis. RESULTS: ALK+ NSCLC cells exhibited significantly higher levels of glycolysis compared to ALK- NSCLC cells. Long-term exposure to crizotinib could decrease the sensitivity of ALK+ NSCLC cells to crizotinib via increasing the levels of glycolysis related to hexokinases II (HK2). Crizotinib in combination with glycolysis inhibitor 2-deoxy-D-glucose (2DG) synergistically inhibited proliferation, glycolysis, colony formation and invasion ability of ALK+ NSCLC cells. 2DG sensitization crizotinib might be associated with the inhibition of HK2-mediated glycolysis and P-ALK/AKT/mTOR signaling pathway in H3122 and H2228 cells. CONCLUSIONS: These results indicate that HK2-mediated glycolysis plays a crucial role in the increased tolerance of ALK+ NSCLC cells to crizotinib. 2DG may sensitize ALK+ NSCLC to crizotinib via suppression of HK2-mediated glycolysis and the AKT/mTOR signaling pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/farmacologia , Desoxiglucose/farmacologia , Glicólise/efeitos dos fármacos , Hexoquinase/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Quinase do Linfoma Anaplásico/genética , Antimetabólitos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Invasividade Neoplásica , Inibidores de Proteínas Quinases/farmacologia
20.
Nat Commun ; 12(1): 6274, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725361

RESUMO

Cancer cells bearing distinct KRAS mutations exhibit variable sensitivity to SHP2 inhibitors (SHP2i). Here we show that cells harboring KRAS Q61H are uniquely resistant to SHP2i, and investigate the underlying mechanisms using biophysics, molecular dynamics, and cell-based approaches. Q61H mutation impairs intrinsic and GAP-mediated GTP hydrolysis, and impedes activation by SOS1, but does not alter tyrosyl phosphorylation. Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells. Phosphorylation of wild-type and Gly12-mutant KRAS, which are associated with sensitivity to SHP2i, confers resistance to regulation by GAP and GEF activities and impairs binding to RAF, whereas the near-complete GAP/GEF-resistance of KRAS Q61H remains unaltered, and high-affinity RAF interaction is retained. SHP2 can stimulate KRAS signaling by modulating GEF/GAP activities and dephosphorylating KRAS, processes that fail to regulate signaling of the Q61H mutant.


Assuntos
Inibidores Enzimáticos/farmacologia , Neoplasias Pulmonares/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Guanosina Trifosfato/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Mutação de Sentido Incorreto , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Quinases raf/genética , Quinases raf/metabolismo , Quinases da Família src/genética , Quinases da Família src/metabolismo
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