scholarly journals Polycyclic Aromatic Hydrocarbon-induced Pulmonary Carcinogenesis in Cytochrome P450 (CYP)1A1- and 1A2-Null Mice: Roles of CYP1A1 and CYP1A2

2020 ◽  
Vol 177 (2) ◽  
pp. 347-361
Author(s):  
Grady Gastelum ◽  
Weiwu Jiang ◽  
Lihua Wang ◽  
Guodong Zhou ◽  
Roshan Borkar ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cytochrome P450 ◽  
Lung Adenocarcinoma ◽  
Tumor Formation ◽  
Human Lung Cancer ◽  
Wild Type ◽  
Polycyclic Aromatic ◽  
Pulmonary Carcinogenesis ◽  
The Individual

Abstract In 2019, lung cancer was estimated to be the leading cause of cancer deaths in humans. Polycyclic aromatic hydrocarbons (PAHs) are known to increase the risk of lung cancer. PAHs are metabolized by the cytochrome P450 (CYP)1A subfamily, comprised of the CYP1A1 and 1A2 monooxygenases. These enzymes bioactivate PAHs into reactive metabolites that induce mutagenic DNA adducts, which can lead to cancer. Past studies have investigated the role of CYP1A1 in PAH bioactivation; however, the individual roles of each CYP1A enzyme are still unknown. In this investigation, we tested the hypothesis that mice lacking the genes for Cyp1a1 or Cyp1a2 will display altered susceptibilities to PAH-induced pulmonary carcinogenesis. Wild-type, Cyp1a1-null (Cyp1a1−/−), and Cyp1a2-null (Cyp1a2−/−) male and female mice were treated with 3-methylcholanthrene for cancer initiation and tumor formation studies. In wild-type mice, CYP1A1 and 1A2 expression was induced by 3-methylcholanthrene. Cyp1a1−/− and Cyp1a2−/− mice treated with PAHs displayed a compensatory pattern, where knocking out 1 Cyp1a gene led to increased expression of the other. Cyp1a1−/− mice were resistant to DNA adduct and tumor formation, whereas Cyp1a2−/− mice displayed increased levels of both. UALCAN analysis revealed that lung adenocarcinoma patients with high levels of CYP1A2 expression survive significantly better than patients with low/medium expression. In conclusion, Cyp1a1−/− mice were less susceptible to PAH-induced pulmonary carcinogenesis, whereas Cyp1a2−/− mice were more susceptible. In addition, high CYP1A2 expression was found to be protective for lung adenocarcinoma patients. These results support the need to develop novel CYP1A1 inhibitors to mitigate human lung cancer.

Isoorientin Decreases Cell Migration via Decreasing Functional Activity and Molecular Expression of Proton-Linked Monocarboxylate Transporters in Human Lung Cancer Cells

2020 ◽  
Vol 48 (01) ◽  
pp. 201-222
Author(s):  
Hsu-Kai Huang ◽  
Shin-Yi Lee ◽  
Shu-Fen Huang ◽  
Yu-San Lin ◽  
Shih-Chi Chao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Migration ◽  
Lung Adenocarcinoma ◽  
Cell Viability ◽  
Cancer Cells ◽  
Functional Activity ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Human Lung Cancer Cells

Aggressive tumor cells mainly rely on glycolysis, and further release vast amounts of lactate and protons by monocarboxylate transporter (MCT), which causes a higher intracellular pH (pHi) and acidic extracellular pH. Isoorientin, a principle flavonoid compound extracted from several plant species, shows various pharmacological activities. However, effects of isoorientin on anticancer and MCT await to explore in human lung cancer cells. Human lung cancer tissues were obtained from cancer patients undergoing surgery, while the human lung adenocarcinoma cells (A549) were bought commercially. Change of pHi was detected by microspectrofluorometry method with a pH-sensitive fluorescent dye, BCECF. MTT and wound-healing assay were used to detect the cell viability and migration, respectively. Western blot techniques and immunocytochemistry staining were used to detect the protein expression. Our results indicated that the expression of MCTs1/4 and CD147 were upregulated significantly in human lung tissues. In experiments of A549 cells, under HEPES-buffer, the resting pHi was 7.47, and isoorientin (1–300[Formula: see text][Formula: see text]M) inhibited functional activity of MCT concentration-dependently (up to [Formula: see text]%). Pretreatment with isoorientin (3–100[Formula: see text][Formula: see text]M) for 24[Formula: see text]h, MCT activity and cell migration were significantly inhibited ([Formula: see text]% and [Formula: see text]%, respectively), while the cell viability was not affected. Moreover, the expression of MCTs1/4, CD147, and matrix metalloproteinase (MMP) 2/9 were significantly down regulated. In summary, MCTs1/4 and CD147 are significantly upregulated in human lung adenocarcinoma tissues, and isoorientin inhibits cells-migration by inhibiting activity/expression of MCTs1/4 and MMPs2/9 in human lung cancer cells. These novel findings suggest that isoorientin could be a promising pharmacological agent for lung cancer.

scholarly journals Cisplatin-induced hydroxyl radicals mediate pro-survival autophagy in human lung cancer H460 cells

2021 ◽  
Vol 54 (1) ◽  
Author(s):  
Somruethai Sumkhemthong ◽  
Eakachai Prompetchara ◽  
Pithi Chanvorachote ◽  
Chatchai Chaotham
Keyword(s):  
Lung Cancer ◽  
Hydroxyl Radicals ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Radical Scavenger ◽  
Apoptosis Resistance ◽  
Lung Cancer Patients ◽  
Human Lung Cancer Cells ◽  
H460 Cells

Abstract Background Accumulated evidence demonstrates cisplatin, a recommended chemotherapy, modulating pro-survival autophagic response that contributes to treatment failure in lung cancer patients. However, distinct mechanisms involved in cisplatin-induced autophagy in human lung cancer cells are still unclear. Results Herein, role of autophagy in cisplatin resistance was indicated by a decreased cell viability and increased apoptosis in lung cancer H460 cells pre-incubated with wortmannin, an autophagy inhibitor, prior to treatment with 50 µM cisplatin for 24 h. The elevated level of hydroxyl radicals detected via flow-cytometry corresponded to autophagic response, as evidenced by the formation of autophagosomes and autolysosomes in cisplatin-treated cells. Interestingly, apoptosis resistance, autophagosome formation, and the alteration of the autophagic markers, LC3-II/LC3-I and p62, as well as autophagy-regulating proteins Atg7 and Atg3, induced by cisplatin was abrogated by pretreatment of H460 cells with deferoxamine, a specific hydroxyl radical scavenger. The modulations in autophagic response were also indicated in the cells treated with hydroxyl radicals generated via Fenton reaction, and likewise inhibited by pretreatment with deferoxamine. Conclusions In summary, the possible role of hydroxyl radicals as a key mediator in the autophagic response to cisplatin treatment, which was firstly revealed in this study would benefit for the further development of novel therapies for lung cancer.

scholarly journals Targeting HSPA1A in ARID2-deficient lung adenocarcinoma

2021 ◽  
Author(s):  
Xue Wang ◽  
Yuetong Wang ◽  
Zhaoyuan Fang ◽  
Hua Wang ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Genetically Engineered ◽  
Malignant Progression ◽  
Murine Models ◽  
Rna Seq ◽  
Potential Therapeutic Target ◽  
Lung Cancers ◽  
Integrative Analyses

Abstract Somatic mutations of the chromatin remodeling gene ARID2 are observed in about 7% of human lung adenocarcinoma (LUAD). However, the role of ARID2 in the pathogenesis of LUAD remains largely unknown. Here we find that ARID2 expression is decreased during the malignant progression of both human and mice LUAD. Using two KrasG12D-based genetically engineered murine models (GEMM), we demonstrate that ARID2 knockout significantly promotes lung cancer malignant progression and shortens the overall survival. Consistently, ARID2 knockdown significantly promotes cell proliferation in human and mice lung cancer cells. Through integrative analyses of Chip-Seq and RNA-Seq data, we find that Hspa1a is up-regulated by Arid2 loss. Knockdown of Hspa1a specifically inhibits malignant progression of Arid2-deficient but not Arid2-wt lung cancers in both cell lines as well as animal models. Treatment with Hspa1a inhibitor could significantly inhibit the malignant progression of lung cancer with Arid2 deficiency. Together, our findings establish ARID2 as an important tumor suppressor in LUAD with novel mechanistic insights, and further identify HSPA1A as a potential therapeutic target in ARID2-deficient LUAD.

Proteomic and redox-proteomic study on the role of glutathione reductase in human lung cancer cells

2013 ◽  
Vol 34 (24) ◽  
pp. 3305-3314 ◽  
Author(s):  
Chiao-Yuan Fan ◽  
Hsiu-Chuan Chou ◽  
Yi-Wen Lo ◽  
Yueh-Feng Wen ◽  
Yi-Chih Tsai ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Glutathione Reductase ◽  
Cancer Cells ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Human Lung Cancer Cells ◽  
Proteomic Study

scholarly journals Role of Cytochrome P450 3A4 and 1A2 Phenotyping in Patients with Advanced Non-small-Cell Lung Cancer Receiving Erlotinib Treatment

2017 ◽  
Vol 121 (4) ◽  
pp. 309-315 ◽  
Author(s):  
Zinnia P. Parra-Guillen ◽  
Peter B. Berger ◽  
Manuel Haschke ◽  
Massimiliano Donzelli ◽  
Daria Winogradova ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cytochrome P450 ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Cytochrome P450 3A4 ◽  
Small Cell Lung

scholarly journals Requirement for PKC Epsilon in Kras-Driven Lung Tumorigenesis

2020 ◽  
Author(s):  
Rachana Garg ◽  
Mariana Cooke ◽  
Shaofei Wang ◽  
Fernando Benavides ◽  
Martin C. Abba ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Cancer Therapeutics ◽  
Rna Seq ◽  
Lung Tumorigenesis ◽  
Mechanistic Analysis ◽  
Oncogenic Driver ◽  
Histological Form

ABSTRACTNon-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCε, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCε expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCε-deficient, conditionally activatable allele of oncogenic Kras (LSL-KrasG12D;PKCε−/− mice) we were able to demonstrate the requirement of PKCε for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCε-deficient KRAS-dependent NSCLC cells. Moreover, PKCε-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCε and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCε in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCε for lung cancer therapeutics.

scholarly journals Leukotriene B4 receptor-2 contributes to KRAS-driven lung tumor formation by promoting interleukin-6-mediated inflammation

2021 ◽  
Author(s):  
Jae-Hyun Jang ◽  
Donghwan Park ◽  
Guen-soo Park ◽  
Dong-Wook Kwak ◽  
JaeIn Park ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Interleukin 6 ◽  
Double Mutant ◽  
Lung Tumor ◽  
Leukotriene B4 ◽  
Tumor Formation ◽  
Human Lung Cancer ◽  
Specific Expression ◽  
Tissue Samples ◽  
Attractive Therapeutic Target

AbstractAlthough lung cancer is the leading cause of cancer-related deaths worldwide and KRAS is the most frequently mutated oncogene in lung cancer cases, the mechanism by which KRAS mutation drives lung cancer has not been fully elucidated. Here, we report that the expression levels of leukotriene B4 receptor-2 (BLT2) and its ligand-producing enzymes (5-LOX, 12-LOX) were highly increased by mutant KRAS and that BLT2 or 5-/12-LOX blockade attenuated KRAS-driven lung cell proliferation and production of interleukin-6 (IL-6), a principal proinflammatory mediator of lung cancer development. Next, we explored the roles of BLT2 and 5-/12-LOX in transgenic mice with lung-specific expression of mutant KRAS (KrasG12D) and observed that BLT2 or 5-/12-LOX inhibition decreased IL-6 production and tumor formation. To further determine whether BLT2 is involved in KRAS-driven lung tumor formation, we established a KrasG12D/BLT2-KO double-mutant mouse model. In the double-mutant mice, we observed significantly suppressed IL-6 production and lung tumor formation. Additionally, we observed high BLT2 expression in tissue samples from patients with KrasG12D-expressing lung adenocarcinoma, supporting the contributory role of BLT2 in KRAS-driven human lung cancer. Collectively, our results suggest that BLT2 is a potential contributor to KRAS-driven lung cancer and identify an attractive therapeutic target for KRAS-driven lung cancer.

scholarly journals The Oncogenic Potential of a Mutant TP53 Gene Explored in Two Spontaneous Lung Cancer Mice Models

2020 ◽  
Author(s):  
Julian Ramelow ◽  
Christopher Brooks ◽  
Li GaO ◽  
Abeer A Almiman ◽  
Terence M Williams ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Models ◽  
Human Lung ◽  
Lung Tumor ◽  
Mutant Gene ◽  
Genetic Mutation ◽  
Tumor Formation ◽  
Human Lung Cancer ◽  
Oncogenic Potential ◽  
Age Related

Abstract BackgroundLung cancer is the number one cancer killer worldwide. A major impediment to progress in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor suppressor gene TP53 are among the most common alterations in human lung cancers.MethodsPreviously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H.ResultsWe found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents.ConclusionsOncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune check point inhibitors or other therapeutic strategies in treatment of lung cancer.

scholarly journals miR-200 deficiency promotes lung cancer metastasis by activating cancer-associated fibroblasts

2020 ◽  
Author(s):  
Bin Xue ◽  
Chen-Hua Chuang ◽  
Haydn M. Prosser ◽  
Cesar Seigi Fuziwara ◽  
Claudia Chan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Lung Cancer Mortality ◽  
Tumor Stroma ◽  
Metastatic Potential ◽  
Human Lung Cancer ◽  
Cancer Associated Fibroblasts

AbstractLung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying cellular and molecular mechanisms remain largely elusive. Here, we identified miR-200 miRNAs as potent suppressors for lung adenocarcinoma metastasis. miR-200 expression is specifically repressed in mouse metastatic lung adenocarcinomas, and miR-200 decrease strongly correlates with poor patient survival. Consistently, deletion of mir-200c/141 in the KrasLSL-G12D/+; Trp53flox/flox lung adenocarcinoma mouse model significantly promoted metastasis, generating a desmoplastic tumor stroma highly reminiscent of metastatic human lung cancer. miR-200 deficiency in lung cancer cells promotes the proliferation and activation of adjacent cancer-associated fibroblasts (CAFs), which in turn elevates the metastatic potential of cancer cells. miR-200 regulates the functional interaction between cancer cells and CAFs, at least in part, by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs. Hence, the interaction between cancer cells and CAFs constitutes an essential mechanism to promote metastatic potential.

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