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1.
iScience ; 27(7): 110137, 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-39006481

ABSTRACT

Pituitary adenoma-induced excess endocrine growth hormone (GH) secretion can lead to breast cancer development and metastasis. Herein, we used an acromegaly mouse model to investigate the role of excess endocrine GH on triple-negative breast cancer (TNBC) growth and metastasis. Additionally, we aimed to elucidate the molecular mechanism of transcription factor 20 (TCF20)/nuclear factor erythroid 2-related factor 2 (NRF2) signaling-mediated aggressiveness and metastasis of TNBC. Excess endocrine GH induced TCF20 activates the transcription of NRF2 and NRF2-target genes to facilitate TNBC metastasis. Inhibition of GH receptor (GHR) and TCF20 activity using the GHR antagonist or small-interfering RNA-induced gene knockdown resulted in reduced tumor volume and metastasis, suggesting that excess endocrine GH stimulates TCF20/NRF2 pathways in TNBC and promotes metastasis to the lung. GHR inhibitors present an effective therapeutic strategy to prevent TNBC cell growth and metastasis. Our findings revealed functional and mechanistic roles of the GH-TCF20-NRF2 signaling axis in TBNC progression.

2.
Biomedicines ; 11(6)2023 Jun 11.
Article in English | MEDLINE | ID: mdl-37371783

ABSTRACT

Medullary thyroid cancer originates from parafollicular C-cells in the thyroid. Despite successful thyroidectomy, localizing remnant cancer cells in patients with elevated calcitonin and carcinoembryonic antigen levels remains a challenge. Extranasal odorant receptors are expressed in cells from non-olfactory tissues, including C-cells. This study evaluates the odorant receptor signals from parafollicular C-cells, specifically, the presence of olfactory marker protein, and further assesses the ability of the protein in localizing and treating medullary thyroid cancer. We used immunohistochemistry, immunofluorescent staining, Western blot, RNA sequencing, and real time-PCR to analyze the expression of odorant receptors in mice thyroids, thyroid cancer cell lines, and patient specimens. We used in vivo assays to analyze acetate binding, calcitonin secretion, and cAMP pathway. We also used positron emission tomography (PET) to assess C11-acetate uptake in medullary thyroid cancer patients. We investigated olfactory marker protein expression in C-cells in patients and found that it co-localizes with calcitonin in C-cells from both normal and cancer cell lines. Specifically, we found that OR51E2 and OR51E1 were expressed in thyroid cancer cell lines and human medullary thyroid cancer cells. Furthermore, we found that in the C-cells, the binding of acetate to OR51E2 activates its migration into the nucleus, subsequently resulting in calcitonin secretion via the cAMP pathway. Finally, we found that C11-acetate, a positron emission tomography radiotracer analog for acetate, binds competitively to OR51E2. We confirmed C11-acetate uptake in cancer cells and in human patients using PET. We demonstrated that acetate binds to OR51E2 in C-cells. Using C11-acetate PET, we identified recurrence sites in post-operative medullary thyroid cancer patients. Therefore, OR51E2 may be a novel diagnostic and therapeutic target for medullary thyroid cancer.

3.
Mol Cell Endocrinol ; 575: 111992, 2023 09 15.
Article in English | MEDLINE | ID: mdl-37328092

ABSTRACT

Olfactory marker protein (OMP) regulates olfactory transduction and is also expressed in adipose tissue. Since it serves as a regulatory buffer for cyclic AMP (cAMP) levels, we hypothesized that it plays a role in modulating adipocyte differentiation. To determine the role of OMP in adipogenesis, we examined the differences in body weight, adipose tissue mass, and adipogenic or thermogenic gene expression between high-fat diet-fed control and Omp-knockout (KO) mice. cAMP production, adipogenic gene expression, and cAMP response element binding protein (CREB) phosphorylation were measured during the differentiation of 3T3-L1 preadipocytes and mouse embryonic fibroblasts (MEFs). RNA sequencing was performed to determine the gene expression patterns responsible for the reduction in adipogenesis when Omp was deleted. Body weight, adipose tissue mass, and adipocyte size decreased in Omp-KO mice. Furthermore, cAMP production and CREB phosphorylation reduced during adipogenesis induced in Omp-/- MEFs, and the Nuclear factor kappa B was activated due to significantly reduced expression of its inhibitor. Collectively, our results suggest that loss of OMP function inhibits adipogenesis by affecting adipocyte differentiation.


Subject(s)
Adipogenesis , Cyclic AMP , Animals , Mice , 3T3-L1 Cells , Adipogenesis/genetics , Body Weight , Cell Differentiation , Fibroblasts , NF-KappaB Inhibitor alpha , Olfactory Marker Protein
4.
Exp Mol Med ; 54(9): 1502-1510, 2022 09.
Article in English | MEDLINE | ID: mdl-36104518

ABSTRACT

The olfactory marker protein (OMP), which is also expressed in nonolfactory tissues, plays a role in regulating the kinetics and termination of olfactory transduction. Thus, we hypothesized that OMP may play a similar role in modulating the secretion of hormones involved in Ca2+ and cAMP signaling, such as glucagon. In the present study, we confirmed nonolfactory α-cell-specific OMP expression in human and mouse pancreatic islets as well as in the murine α-cell line αTC1.9. Glucagon and OMP expression increased under hyperglycemic conditions. Omp knockdown in hyperglycemic αTC1.9 cells using small-interfering RNA (siRNA) reduced the responses to glucagon release and the related signaling pathways compared with the si-negative control. The OMPlox/lox;GCGcre/w mice expressed basal glucagon levels similar to those in the wild-type OMPlox/lox mice but showed resistance against streptozotocin-induced hyperglycemia. The ectopic olfactory signaling events in pancreatic α-cells suggest that olfactory receptor pathways could be therapeutic targets for reducing excessive glucagon levels.


Subject(s)
Hyperglycemia , Receptors, Odorant , Animals , Glucagon , Humans , Hyperglycemia/genetics , Mice , Olfactory Marker Protein/genetics , RNA, Small Interfering/genetics , Receptors, Odorant/genetics , Streptozocin
5.
Front Endocrinol (Lausanne) ; 13: 937394, 2022.
Article in English | MEDLINE | ID: mdl-35909546

ABSTRACT

The Roux-en-Y gastric bypass (RYGB) is highly effective in the remission of obesity and associated diabetes. The mechanisms underlying obesity and type 2 diabetes mellitus remission after RYGB remain unclear. This study aimed to evaluate the changes in continuous dynamic FDG uptake patterns after RYGB and examine the correlation between glucose metabolism and its transporters in variable endocrine organs using 18F-fluoro-2-deoxyglucose positron emission tomography images. Increased glucose metabolism in specific organs, such as the small intestine and various fat tissues, is closely associated with improved glycemic control after RYGB. In Otsuka Long-Evans Tokushima Fatty rats fed with high-fat diets, RYGB operation increases intestine glucose transporter expression and various fat tissues' glucose transporters, which are not affected by insulin. The fasting glucose decrement was significantly associated with RYGB, sustained weight loss, post-RYGB oral glucose tolerance test (OGTT) area under the curve (AUC), glucose transporter, or glycolytic enzymes in the small bowel and various fat tissues. High intestinal glucose metabolism and white adipose tissue-dependent glucose metabolism correlated with metabolic benefit after RYGB. These findings suggest that the newly developed glucose biodistribution accompanied by increased glucose transporters is a mechanism associated with the systemic effect of RYGB.


Subject(s)
Bariatric Surgery , Diabetes Mellitus, Type 2 , Gastric Bypass , Animals , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/surgery , Gastric Bypass/methods , Glucose/metabolism , Glucose Transport Proteins, Facilitative/metabolism , Obesity/metabolism , Obesity/surgery , Rats , Tissue Distribution
6.
J Mol Endocrinol ; 68(1): 51-62, 2021 11 26.
Article in English | MEDLINE | ID: mdl-34738916

ABSTRACT

Expression of aberrant microRNA (miRNA) is associated with tumour formation, migration, and invasion. However, there is limited information about the epigenetics of pituitary tumorigenesis. This study investigated the role of miRNA expression during the tumorigenesis of growth hormone (GH)-secreting pituitary tumours. miRNA profiling and real-time PCR were used to analyse the mRNA expression profile in sequential pituitary tissues of a unique animal model with a GH-producing pituitary tumour. Selected miRNAs were further validated in GH-producing cell lines and human pituitary tumour samples. The expression of significantly altered miRNAs and their predicted targets, as detected by microarray, was evaluated by real-time PCR, Western blotting, and immunohistochemistry using samples from mouse models and human pituitary tumours. The effect of miRNAs on tumour proliferation and invasion was examined in GH3 cells using the MTS and Matrigel invasion assays. Among the 14 miRNAs whose expression was significantly changed, miR-216a-5p (fold change = -5.638, P -value = 0.014) and miR-652-3p (fold change = -3.482, P -value = 0.010) were constantly and significantly downregulated. Transfection with mimics of miR-216a-5p and miR-652-3p inhibited GH3 proliferation and invasion, whereas inhibitors promoted them. The direct target genes of miR-216a-5p and miR-652-3p were Jak2 and Prrx1, respectively, which were downregulated in GH3 cells transfected with mimics and in serial pituitary gland tissues, including hyperplasic tissues and tumours of acromegalic animal models and pituitary tumour tissues of acromegalic patients. Downregulated miR-216a-5p and miR-652-3p expression may contribute to tumour progression by targeting JAK2 and PRRX1 on GH-producing pituitary tumours.


Subject(s)
Growth Hormone/biosynthesis , Homeodomain Proteins/genetics , Janus Kinase 2/genetics , MicroRNAs/genetics , Pituitary Neoplasms/etiology , Pituitary Neoplasms/metabolism , Animals , Cell Line, Tumor , Disease Models, Animal , Gene Expression Regulation , Humans , Janus Kinase 2/metabolism , Mice , Pituitary Neoplasms/pathology
7.
Gut ; 70(10): 1847-1856, 2021 10.
Article in English | MEDLINE | ID: mdl-33208408

ABSTRACT

OBJECTIVE: The mechanisms underlying type 2 diabetes resolution after Roux-en-Y gastric bypass (RYGB) are unclear. We suspected that glucose excretion may occur in the small bowel based on observations in humans. The aim of this study was to evaluate the mechanisms underlying serum glucose excretion in the small intestine and its contribution to glucose homeostasis after bariatric surgery. DESIGN: 2-Deoxy-2-[18F]-fluoro-D-glucose (FDG) was measured in RYGB-operated or sham-operated obese diabetic rats. Altered glucose metabolism was targeted and RNA sequencing was performed in areas of high or low FDG uptake in the ileum or common limb. Intestinal glucose metabolism and excretion were confirmed using 14C-glucose and FDG. Increased glucose metabolism was evaluated in IEC-18 cells and mouse intestinal organoids. Obese or ob/ob mice were treated with amphiregulin (AREG) to correlate intestinal glycolysis changes with changes in serum glucose homeostasis. RESULTS: The AREG/EGFR/mTOR/AKT/GLUT1 signal transduction pathway was activated in areas of increased glycolysis and intestinal glucose excretion in RYGB-operated rats. Intraluminal GLUT1 inhibitor administration offset improved glucose homeostasis in RYGB-operated rats. AREG-induced signal transduction pathway was confirmed using IEC-18 cells and mouse organoids, resulting in a greater capacity for glucose uptake via GLUT1 overexpression and sequestration in apical and basolateral membranes. Systemic and local AREG administration increased GLUT1 expression and small intestinal membrane translocation and prevented hyperglycaemic exacerbation. CONCLUSION: Bariatric surgery or AREG administration induces apical and basolateral membrane GLUT1 expression in the small intestinal enterocytes, resulting in increased serum glucose excretion in the gut lumen. Our findings suggest a novel, potentially targetable glucose homeostatic mechanism in the small intestine.


Subject(s)
Blood Glucose/metabolism , Fluorodeoxyglucose F18/metabolism , Intestine, Small/metabolism , Amphiregulin/pharmacology , Animals , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Gastric Bypass , Glucose Transporter Type 1/metabolism , Glycolysis , Positron Emission Tomography Computed Tomography , Rats , Rats, Inbred OLETF , Signal Transduction/drug effects
8.
Oncogene ; 39(3): 664-676, 2020 01.
Article in English | MEDLINE | ID: mdl-31534187

ABSTRACT

Integrin beta 4 (ITGB4) overexpression in cancer cells contributes to cancer progression. However, the role of stromal ITGB4 expression in cancer progression remains poorly understood, despite stromal ITGB4 overexpression in malignant cancers. In our study, ITGB4-overexpressing triple negative breast cancer (TNBC) cells provided cancer-associated fibroblasts (CAFs) with ITGB4 proteins via exosomes, which induced BNIP3L-dependent mitophagy and lactate production in CAFs. In coculture assays, the ITGB4-induced mitophagy and glycolysis were suppressed in CAFs by knocking down ITGB4 or inhibiting exosome generation in MDA-MB-231, or blocking c-Jun or AMPK phosphorylation in CAFs. ITGB4-overexpressing CAF-conditioned medium promoted the proliferation, epithelial-to-mesenchymal transition, and invasion of breast cancer cells. In a co-transplant mouse model, MDA-MB-231 made a bigger tumor mass with CAFs than ITGB4 knockdown MDA-MB-231. Herein, we presented how TNBC-derived ITGB4 protein triggers glycolysis in CAFs via BNIP3L-dependent mitophagy and suggested the possibility that ITGB4-induced mitophagy could be targeted as a cancer therapy.


Subject(s)
Cancer-Associated Fibroblasts/pathology , Exosomes/metabolism , Integrin beta4/metabolism , Triple Negative Breast Neoplasms/pathology , Animals , Breast/pathology , Breast/surgery , Cancer-Associated Fibroblasts/metabolism , Cell Line, Tumor , Coculture Techniques , Culture Media, Conditioned , Epithelial-Mesenchymal Transition , Female , Gene Knockdown Techniques , Glycolysis , Humans , Integrin beta4/genetics , Membrane Proteins/metabolism , Mice , Mitophagy , Paracrine Communication , Primary Cell Culture , Proto-Oncogene Proteins/metabolism , Triple Negative Breast Neoplasms/surgery , Tumor Cells, Cultured , Tumor Suppressor Proteins/metabolism , Xenograft Model Antitumor Assays
9.
J Endocr Soc ; 2(11): 1251-1258, 2018 Nov 01.
Article in English | MEDLINE | ID: mdl-30402589

ABSTRACT

Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), produced by intestinal enteroendocrine L cells, are important gut hormones that coordinate gastrointestinal physiology, metabolism, and appetite. We aimed to investigate the role of olfactory receptor (OR) OR51E1 in GLP-1 and PYY secretion. We analyzed the expression of olfactory marker protein (OMP), an indicator of OR-mediated events in nonolfactory systems, in human intestinal L cells. Furthermore, we analyzed OMP and OR51E1 expression in the L cell line NCI-H716. To investigate whether odorant-activated OR signaling stimulates GLP-1 and PYY secretion, we used nonanoic acid, a known OR51E1 ligand. Treatment with 100 µM nonanoic acid increased GLP-1 secretion by 2.32 ± 0.41-fold and PYY secretion by 1.44 ± 0.10-fold; however, this effect was attenuated on small interfering RNA-mediated OR51E1 knockdown. Oral administration of nonanoic acid to rats resulted in a 2.89 ± 0.53-fold increase in GLP-1 levels and reductions in blood glucose levels compared with the control group. Nonanoic acid stimulates GLP-1 and PYY secretion via OR51E1 signaling in L cells, thereby indicating a potential role of OR-mediated events in GLP-1 and PYY secretion; this could be translated into a therapeutic approach in treating diabetes.

10.
Exp Mol Med ; 50(4): 1-11, 2018 04 06.
Article in English | MEDLINE | ID: mdl-29622766

ABSTRACT

Olfactory marker protein (OMP) is a marker of olfactory receptor-mediated chemoreception, even outside the olfactory system. Here, we report that OMP expression in the pituitary gland plays a role in basal and thyrotropin-releasing hormone (TRH)-induced prolactin (PRL) production and secretion. We found that OMP was expressed in human and rodent pituitary glands, especially in PRL-secreting lactotrophs. OMP knockdown in GH4 rat pituitary cells increased PRL production and secretion via extracellular signal-regulated kinase (ERK)1/2 signaling. Real-time PCR analysis and the Ca2+ influx assay revealed that OMP was critical for TRH-induced PRL secretion. OMP-knockout mice showed lower fertility than control mice, which was associated with increased basal PRL production via activation of ERK1/2 signaling and reduced TRH-induced PRL secretion. However, both in vitro and in vivo results indicated that OMP was only required for hormone production and secretion because ERK1/2 activation failed to stimulate cell proliferation. Additionally, patients with prolactinoma lacked OMP expression in tumor tissues with hyperactivated ERK1/2 signaling. These findings indicate that OMP plays a role in PRL production and secretion in lactotrophs through the modulation of Ca2+ and TRH signaling.


Subject(s)
Calcium/metabolism , Lactotrophs/metabolism , Olfactory Marker Protein/metabolism , Prolactin/biosynthesis , Signal Transduction , Thyrotropin-Releasing Hormone/metabolism , Animals , Cell Line , Gene Expression , MAP Kinase Signaling System/drug effects , Male , Mice, Transgenic , Olfactory Marker Protein/genetics , Pituitary Gland/metabolism , Rats , Thyrotropin-Releasing Hormone/blood
11.
Cancer Lett ; 417: 131-140, 2018 03 28.
Article in English | MEDLINE | ID: mdl-29306020

ABSTRACT

The RB-E2F1 pathway is an important mechanism of cell-cycle control, and deregulation of this pathway is one of the key factors contributing to tumorigenesis. Cyclin-dependent kinases (CDKs) and Cyclin D have been known to increase in aggressive thyroid cancer. However, there has been no study to investigate effects of a selective CDK 4/6 inhibitor, Ribociclib (LEE011), in thyroid cancer. Performing Western blotting, we found that RB phosphorylation and the expression of Cyclin D are significantly higher in papillary thyroid cancer (PTC) cell lines as well as anaplastic thyroid cancer (ATC) cell lines, compared with normal thyroid cell line and follicular thyroid cancer cell line. LEE011 dose-dependently inhibited RB phosphorylation and also decreased the expressions of its target genes such as FOXM1, Cyclin A1, and Myc in ATC. Furthermore, LEE011 induced cell cycle arrest in G0-G1 phase and cell apoptosis, and inhibited cell proliferation in ATC. Consistently, oral administration of LEE011 to ATC xenograft models strongly inhibited tumor growth with decreased expressions of pRB, pAKT and Ki-67, and also significantly increased tumor cell apoptosis. Taken together, our data support the rationale for clinical development of the CDK4/6 inhibitor as a therapy for patients with aggressive thyroid cancer.


Subject(s)
Aminopyridines/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Purines/pharmacology , Thyroid Neoplasms/drug therapy , Xenograft Model Antitumor Assays , Animals , Cell Line, Tumor , Cyclin D/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/metabolism , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Male , Mice, Nude , Phosphorylation/drug effects , Retinoblastoma Protein/metabolism , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology
12.
Sci Rep ; 7(1): 14192, 2017 10 27.
Article in English | MEDLINE | ID: mdl-29079748

ABSTRACT

4-Hydroxybenzaldehyde (4-HBA) is a naturally occurring benzaldehyde and the major active constituent of Gastrodia elata. While recent studies have demonstrated metabolic effects of 4-HBA, little is known about the physiological role of 4-HBA in acute wound healing. Here, we investigated the effects and mechanisms of 4-HBA on acute wound healing. Using an in vitro approach, we found that 4-HBA significantly promoted keratinocyte cell migration and invasion by increasing focal adhesion kinase and Src activity. In addition, 4-HBA treatment also promoted wound healing and re-epithelialization in an in vivo excision wound animal model. Combination treatment with 4-HBA and platelet-derived growth factor subunit B homodimer showed synergistic effects in promoting wound healing. Taken together, our results demonstrated that treatment with 4-HBA promoted keratinocyte migration and wound healing in mouse skin through the Src/mitogen-activated protein kinase pathway. Therefore, 4-HBA could be a candidate therapeutic agent with the potential to promote acute wound healing.


Subject(s)
Benzaldehydes/pharmacology , Focal Adhesions/drug effects , Focal Adhesions/metabolism , Keratinocytes/cytology , Keratinocytes/drug effects , Signal Transduction/drug effects , Wound Healing/drug effects , Animals , Becaplermin/pharmacology , Cell Line , Cell Movement/drug effects , Drug Interactions , Gene Expression Regulation/drug effects , Humans , Keratinocytes/metabolism , Mice , Mice, Inbred C57BL , Neovascularization, Physiologic/drug effects , Skin Physiological Phenomena/drug effects , Time Factors
13.
Invest Ophthalmol Vis Sci ; 57(10): 4055-62, 2016 08 01.
Article in English | MEDLINE | ID: mdl-27494347

ABSTRACT

PURPOSE: Protocatechuic aldehyde (3,4-dihydroxybenzaldehyde; PCA) is extracted from Salvia miltiorrhiza, and has been reported to possess antiproliferative, antioxidant, and antiadipogenesis properties in various in vivo and in vitro experiments. This study aimed to outline the antioxidant and suppressive effects of PCA on adipogenesis and hyaluronan production in orbital fibroblasts to help with designing therapeutic approaches for Graves' orbitopathy (GO). METHODS: We assessed the in vitro effects of PCA on orbital fibroblasts, which were cultured from orbital fat tissue obtained from patients undergoing orbital decompression for severe GO. Control tissue was obtained from patients undergoing orbital surgery with no history of GO or Graves' hyperthyroidism. RESULTS: The 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt assay results confirmed the free radical scavenging effect of PCA after treatment. Protocatechuic aldehyde exhibited a suppressive effect on intracellular reactive oxygen species generation and upregulated heme oxygenase-1 expression in Western blot analysis. Protocatechuic aldehyde attenuated TNF-α and IL-1ß-induced hyaluronan production. Oil Red-O staining results revealed a decrease in lipid droplets and suppressed expression of the adipogenesis-related proteins peroxisome proliferator-activated receptor (PPAR)-γ, CCAAT/enhancer binding protein (c/EBP)-α, and c/EBP-ß upon treatment with PCA during adipose differentiation. CONCLUSIONS: In this study, PCA exerted significant antioxidant and antiadipogenic effects and inhibited the production of hyaluronan in GO orbital fibroblasts. Accordingly, PCA potentially could be used as a novel treatment option for GO.


Subject(s)
Benzaldehydes/pharmacology , Catechols/pharmacology , Graves Ophthalmopathy/drug therapy , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Adipocytes/drug effects , Adipocytes/pathology , Anticoagulants/pharmacology , Blotting, Western , Cell Count , Cell Differentiation , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibroblasts/pathology , Graves Ophthalmopathy/metabolism , Graves Ophthalmopathy/pathology , Humans , Orbit/pathology
14.
Mol Cancer Ther ; 15(7): 1627-36, 2016 07.
Article in English | MEDLINE | ID: mdl-27196768

ABSTRACT

Although treatment of BRAF V600E-mutant non-small cell lung cancer (NSCLC(V600E)) with GSK2118436 has shown an encouraging efficacy, most patients develop resistance. To investigate the mechanisms of acquired resistance to GSK2118436 in NSCLC(V600E), we established GSK2118436-resistant (GSR) cells by exposing MV522 NSCLC(V600E) to increasing GSK2118436 concentrations. GSR cells displayed activated EGFR-RAS-CRAF signaling with upregulated EGFR ligands and sustained activation of ERK1/2, but not MEK1/2, in the presence of GSK2118436. Treatment of GSR cells with GSK2118436 enhanced EGFR-mediated RAS activity, leading to the formation of BRAF-CRAF dimers and transactivation of CRAF. Interestingly, sustained activation of ERK1/2 was partly dependent on receptor-interacting protein kinase-2 (RIP2) activity, but not on MEK1/2 activity. Combined BRAF and EGFR inhibition blocked reactivation of ERK signaling and improved efficacy in vitro and in vivo Our findings support the evaluation of combined BRAF and EGFR inhibition in NSCLC(V600E) with acquired resistance to BRAF inhibitors. Mol Cancer Ther; 15(7); 1627-36. ©2016 AACR.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Drug Resistance, Neoplasm/genetics , ErbB Receptors/metabolism , Imidazoles/pharmacology , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , MAP Kinase Signaling System , Mutation , Oximes/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Amino Acid Substitution , Animals , Antineoplastic Agents/pharmacology , Autocrine Communication , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Survival/drug effects , Codon , DNA Mutational Analysis , Disease Models, Animal , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mice , Models, Biological , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Xenograft Model Antitumor Assays , ras Proteins/metabolism
15.
Mol Cancer Ther ; 14(10): 2238-48, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26208525

ABSTRACT

RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G0-G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong antitumor effect of dovitinib was observed in an LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene-set enrichment analysis of gene expression and phosphor-kinase revealed that Src, a central gene in focal adhesion, was activated in LC-2/ad DR cells. Saracatinib, an src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Drug Resistance, Neoplasm , Lung Neoplasms/drug therapy , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Quinolones/pharmacology , Adenocarcinoma/enzymology , Adenocarcinoma/pathology , Adenocarcinoma of Lung , Animals , Antineoplastic Agents/chemistry , Apoptosis , Benzimidazoles/chemistry , Catalytic Domain , Cell Cycle Checkpoints , Cell Line, Tumor , Enzyme Activation , HEK293 Cells , Humans , Inhibitory Concentration 50 , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Mice, Nude , Models, Molecular , Protein Kinase Inhibitors , Proto-Oncogene Proteins c-ret/chemistry , Quinolones/chemistry , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , src-Family Kinases/metabolism
16.
Eur J Cancer ; 51(12): 1588-95, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26070683

ABSTRACT

BACKGROUND: This phase 2 study investigated the efficacy and safety of dovitinib (TKI258), a receptor tyrosine kinase inhibitor with potent activity against fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR), in locally advanced or metastatic thyroid cancer patients. PATIENTS AND METHODS: Patients with advanced thyroid cancer that was refractory or not appropriate for (131)I received dovitinib orally, 500mg once daily for five consecutive days, followed by a 2-day rest every week. The primary end-point was objective response rate. Secondary end-points were progression-free survival (PFS), overall survival (OS), duration of response, changes in tumour markers and safety. RESULTS: Between January 2013 and October 2014, a total of 40 patients were enrolled. There were 23 (57.5%) papillary thyroid cancer, 12 (30%) medullary thyroid cancer and 5 (12.5%) follicular thyroid cancer patients. One patient had withdrawn consent before the administration of dovitinib. The overall response rate was 20.5% (8/39) and disease control rate was 69.1% (26/39). Median PFS was 5.4 months (95% confidence interval (CI), 2.0-8.8) and median OS was not reached with 8.4 months follow-up duration. Common treatment-related adverse events were diarrhoea (53.8%), anorexia (35.8%), vomiting (25.6%), fatigue (23%) and nausea (20.5%), most of which were grade 1 or 2. There were no grade 4 events or treatment-related deaths. Dose interruption occurred in 12 (30.7%) patients, and 19 (48.7%) patients experienced dose reduction due to adverse events. CONCLUSIONS: Dovitinib has a modest activity with manageable toxicity in locally advanced or metastatic thyroid cancer.


Subject(s)
Antineoplastic Agents/therapeutic use , Benzimidazoles/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Quinolones/therapeutic use , Thyroid Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Female , Humans , Male , Middle Aged , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Survival Analysis , Thyroid Neoplasms/metabolism , Vascular Endothelial Growth Factor A/antagonists & inhibitors
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