Targeting Nicotinamide N-Methyltransferase and miR-449a in EGFR-TKI-Resistant Non-Small-Cell Lung Cancer Cells

Bach, Duc-Hiep; Kim, Donghwa; Bae, Song Yi; Kim, Won Kyung; Hong, Ji‐Young; Lee, Hyejung; Rajasekaran, Nirmal; Kwon, Soonbum; Fan, Yanhua; Luu, Thi-Thu-Trang; Shin, Young Kee; Lee, Jeeyeon; Lee, Sang Kook

doi:10.1016/j.omtn.2018.03.011

Cited by 60 publications

(58 citation statements)

References 44 publications

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“…Resistance to anticancer drugs is a complex process (5,(95)(96)(97)(98)(99)(100)(101)(102), and CIN-related phenotypic and genetic diversity in tumors has implications for chemotherapy-resistance including innate and acquired resistance (89). CIN-positive tumors seem to be more sensitive to DNA-damaging agents or radiotherapy (6) stability by using inhibitors of the microtubule-destabilizing kinase, Aurora B (104), may enhance chromosome missegregation; Aurora B inhibitors have shown efficacy in primary as well as taxane-resistant tumors (105,106).…”

Section: Combination With Chemotherapy To Overcome Resistancementioning

confidence: 99%

Chromosomal Instability in Tumor Initiation and Development

2019

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Chromosomal instability (CIN) is one of the major forms of genomic instability in various human cancers and is recognized as a common hallmark of tumorigenesis and heterogeneity. However, some malignant tumors show a paucity of chromosomal alterations, suggesting that tumor progression and evolution can occur in the absence of CIN. It is unclear whether CIN is stable between precursor lesions, primary tumor, and metastases or if it evolves during these steps. In this review, we describe the influence of CIN on the various steps in tumor initiation and development. Given the recognized significant effects of CIN in cancer, CIN-targeted therapeutics could have a major impact on improving clinical outcomes.

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Section: Combination With Chemotherapy To Overcome Resistancementioning

confidence: 99%

Chromosomal Instability in Tumor Initiation and Development

2019

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“…Indeed, miRNAs may affect genetic programs through post-transcriptional silencing of target genes, either by inhibiting the translation of target mRNAs or by promoting their degradation 16, 17. These actions may lead to the regulation of numerous aspects of cancer biology, including drug resistance, epithelial-to-mesenchymal transition, and metastasis 16, 17, 18…”

Section: Introductionmentioning

confidence: 99%

BMP4 Upregulation Is Associated with Acquired Drug Resistance and Fatty Acid Metabolism in EGFR-Mutant Non-Small-Cell Lung Cancer Cells

Bach

Luu

Kim

et al. 2018

Molecular Therapy - Nucleic Acids

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Lung cancer is the leading cause of cancer-associated deaths worldwide. In particular, non-small-cell lung cancer (NSCLC) cells harboring epidermal growth factor receptor (EGFR) mutations are associated with resistance development of EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. Recent findings suggest that bone morphogenetic proteins (BMPs) and microRNAs (miRNAs) might act as oncogenes or tumor suppressors in the tumor microenvironment. In this study, for the first time, we identified the potential roles of BMPs and miRNAs involved in EGFR-TKI resistance by analyzing datasets from a pair of parental cells and NSCLC cells with acquired EGFR-TKI resistance. BMP4 was observed to be significantly overexpressed in the EGFR-TKI-resistant cells, and its mechanism of action was strongly associated with the induction of cancer cell energy metabolism through the modulation of Acyl-CoA synthetase long-chain family member 4. In addition, miR-139-5p was observed to be significantly downregulated in the resistant NSCLC cells. The combination of miR-139-5p and yuanhuadine, a naturally derived antitumor agent, synergistically suppressed BMP4 expression in the resistant cells. We further confirmed that LDN-193189, a small molecule BMP receptor 1 inhibitor, effectively inhibited tumor growth in a xenograft nude mouse model implanted with the EFGR-TKI-resistant cells. These findings suggest a novel role of BMP4-mediated tumorigenesis in the progression of acquired drug resistance in EGFR-mutant NSCLC cells.

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“…Colony formation assay. The cells were post-transfected with siAGR2 or siRNA control for 48 h. Colony formation analysis was performed according to our previously published procedures (23).…”

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confidence: 99%

“…Immunohistochemistry. Tumor immunohistochemistry analysis was performed according to our previously published procedures (22,23). In brief, sections of the embedded specimens were deparaffinized, rehydrated and subjected to antigen retrieval.…”

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Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

et al. 2020

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Background/Aim: The resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib or erlotinib, is considered a major challenge in the treatment of patients with non-small cell lung cancer (NSCLC). Herein, we identified the critical roles of anterior gradient 2 (AGR2) in gefitinib (Gef) resistance of mutant NSCLC cells. Materials and Methods: Using datasets from a pair of NSCLCsensitive and NSCLC-resistant cells, immunoblotting, immunofluorescence and immunohistochemistry, and cell viability assays were applied to identify the effects of AGR2. Results: AGR2 was found to be significantly over-expressed in Gef-resistant cells and was highly associated with drug resistance, proliferation, migration, and invasion of cancer cells. Moreover, AGR2 and ADAMTS6 formed a negative feedback loop in drug-resistant cells. Conclusion: Modulation of overexpression of AGR2 in mutant NSCLC cells may be an attractive therapeutic strategy for the treatment of EGFR-TKI-resistant NSCLC. Non-small cell lung cancer (NSCLC) is one of the major causes of cancer-related death worldwide, and comprises 85% of all lung cancer cases (1). Acquired drug resistance in tumor cells is a major obstacle in the field of anti-cancer chemotherapies. Likewise, NSCLC patients who initially show a good response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib (Gef), acquire resistance to treatment (2). However, studies on the mechanisms through which overexpression of specific genes is involved in EGFR-TKI resistanse of NSCLC cells are scarce and its role remains to be elucidated. Therefore, novel approaches are required to elucidate their role in drug resistanse of cancer cells. The anterior gradient-2 (AGR2) has been identified in Xenopus laevis and plays a critical role in cemet gland differentiation (3). Recent studies have suggested that elevated expression of AGR2 is correlated with cell proliferation, metastasis, and drug resistance in various human cancer cell lines, such as prostate (4), breast (5), and pancreatic cancer (6). Moreover, overexpression of AGR2 has been notably correlated with a poor outcome of estrogen receptor-negative breast cancer patients (7). AGR2 is also a pro-oncogenic protein that has been shown to stimulate the epidermal growth factor receptor (EGFR) ligand amphiregulin, regulate p53 signaling, and interact with the AAA+ protein Reptin (8), suggesting its modulatory roles in gene expression. High expression of AGR2 has also been shown to be predictive of poor survival in lung cancer (9). However, there is still a lack of insightful understanding of the role of AGR2 in EGFR-TKI-resistant NSCLC cells. There are 19 members of zinc-dependent metalloproteases in the family of a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) (10). Recent reports suggest the critical roles of ADAMTSs in angiogenesis and cancer (11). They also play an important role in the modulation of extracellular matrix. For instance, ADAMTS-1 metallopro...

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Targeting Nicotinamide N-Methyltransferase and miR-449a in EGFR-TKI-Resistant Non-Small-Cell Lung Cancer Cells

Cited by 60 publications

References 44 publications

Chromosomal Instability in Tumor Initiation and Development

Chromosomal Instability in Tumor Initiation and Development

BMP4 Upregulation Is Associated with Acquired Drug Resistance and Fatty Acid Metabolism in EGFR-Mutant Non-Small-Cell Lung Cancer Cells

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

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