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1.
Metabolites ; 13(4)2023 Apr 05.
Article in English | MEDLINE | ID: mdl-37110178

ABSTRACT

Brown adipose tissue (BAT) consumes excess lipids and produces lipid metabolites as ketone bodies. These ketone bodies are then recycled for lipogenesis by the enzyme acetoacetyl-CoA synthetase (AACS). Previously, we found that a high-fat diet (HFD) upregulated AACS expression in white adipose tissue. In this study, we investigated the effects of diet-induced obesity on AACS in BAT. When 4-week-old ddY mice were fed a HFD or high-sucrose diet (HSD) for 12 weeks, a significant decrease in Aacs, acetyl-CoA carboxylase-1 (Acc-1), and fatty acid synthase (Fas) expression was observed in the BAT of the HFD group, whereas expression was not affected in the HSD group. In vitro analysis showed decreased Aacs and Fas expression in rat primary-cultured brown adipocytes following isoproterenol treatment for 24 h. In addition, the suppression of Aacs by siRNA markedly decreased the expression of Fas and Acc-1 but did not affect the expression of uncoupling protein-1 (UCP-1) or other factors. These results suggested that HFD may suppress ketone body utilization for lipogenesis in BAT and that AACS gene expression may be important for regulating lipogenesis in BAT. Therefore, the AACS-mediated ketone body utilization pathway may regulate lipogenesis under conditions of excess dietary fat.

2.
Biol Pharm Bull ; 46(5): 661-671, 2023 May 01.
Article in English | MEDLINE | ID: mdl-36948634

ABSTRACT

Myelosuppression, a side effect of anticancer drugs, makes people more susceptible to infectious diseases by compromising the immune system. When a cancer patient develops a contagious disease, treatment with an anticancer drug is suspended or postponed to treat the infectious disease. If there was a drug that suppresses the growth of cancer cells among antibacterial agents, it would be possible to treat both infectious diseases and cancer. Therefore, this study investigated the effect of antibacterial agents on cancer cell development. Vancomycin (VAN) had little effect on cell proliferation against the breast cancer cell, MCF-7, prostate cancer cell, PC-3, and gallbladder cancer cell, NOZ C-1. Alternatively, Teicoplanin (TEIC) and Daptomycin (DAP) promoted the growth of some cancer cells. In contrast, Linezolid (LZD) suppressed the proliferation of MCF-7, PC-3, and NOZ C-1 cells. Therefore, we found a drug that affects the growth of cancer cells among antibacterial agents. Next, when we examined the effects of the combined use of existing anticancer and antibacterial agents, we found VAN did not affect the growth suppression by anticancer agents. However, TEIC and DAP attenuated the growth suppression of anticancer agents. In contrast, LZD additively enhanced the growth suppression by Docetaxel in PC-3 cells. Furthermore, we showed that LZD inhibits cancer cell growth by mechanisms that involve phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway suppression. Therefore, LZD might simultaneously treat cancer and infectious diseases.


Subject(s)
Daptomycin , Prostatic Neoplasms , Male , Humans , Anti-Bacterial Agents/therapeutic use , Phosphatidylinositol 3-Kinases , Linezolid/pharmacology , Vancomycin/pharmacology , Proto-Oncogene Proteins c-akt , Prostatic Neoplasms/drug therapy , Cell Proliferation
3.
Bioorg Med Chem ; 82: 117214, 2023 03 15.
Article in English | MEDLINE | ID: mdl-36913882

ABSTRACT

Retinoic acid (RA, 1), an oxidized form of vitamin A, binds to retinoic acid receptors (RAR) and retinoid X receptors (RXR) to regulate gene expression and has important functions such as cell proliferation and differentiation. Synthetic ligands regarding RAR and RXR have been devised for the treatment of various diseases, particularly promyelocytic leukemia, but their side effects have led to the development of new, less toxic therapeutic agents. Fenretinide (4-HPR, 2), an aminophenol derivative of RA, exhibits potent antiproliferative activity without binding to RAR/RXR, but its clinical trial was discontinued due to side effects of impaired dark adaptation. Assuming that the cyclohexene ring of 4-HPR is the cause of the side effects, methylaminophenol was discovered through structure-activity relationship research, and p-dodecylaminophenol (p-DDAP, 3), which has no side effects or toxicity and is effective against a wide range of cancers, was developed. Therefore, we thought that introducing the motif carboxylic acid found in retinoids, could potentially enhance the anti-proliferative effects. Introducing chain terminal carboxylic functionality into potent p-alkylaminophenols significantly attenuated antiproliferative potencies, while a similar structural modification of weakly potent p-acylaminophenols enhanced growth inhibitory potencies. However, conversion of the carboxylic acid moieties to their methyl esters completely abolished the cell growth inhibitory effects of both series. Insertion of a carboxylic acid moiety, which is important for binding to RA receptors, abolishes the action of p-alkylaminophenols, but enhances the action of p-acylaminophenols. This suggests that the amido functionality may be important for the growth inhibitory effects of the carboxylic acids.


Subject(s)
Antineoplastic Agents , Fenretinide , Retinoids/pharmacology , Retinoids/chemistry , Aminophenols , Antineoplastic Agents/pharmacology , Tretinoin/pharmacology , Retinoid X Receptors
4.
Pharmacol Ther ; 230: 107942, 2022 02.
Article in English | MEDLINE | ID: mdl-34175370

ABSTRACT

Vitamin A is an important micro-essential nutrient, whose primary dietary source is retinyl esters. In addition, ß-carotene (pro-vitamin A) is a precursor of vitamin A contained in green and yellow vegetables that is converted to retinol in the body after ingestion. Retinol is oxidized to produce visual retinal, which is further oxidized to retinoic acid (RA), which is used as a therapeutic agent for patients with promyelocytic leukemia. Thus, the effects of retinal and RA are well known. In this paper, we will introduce (1) vitamin A circulation in the body, (2) the actions and mechanisms of retinal and RA, (3) retinoylation: another RA mechanism not depending on RA receptors, (4) the relationship between cancer and actions of retinol or ß-carotene, whose roles in vivo are still unknown, and (5) anti-cancer actions of vitamin A derivatives derived from fenretinide (4-HPR). We propose that vitamin A nutritional management is effective in the prevention of cancer.


Subject(s)
Neoplasms , Vitamin A , Cell Differentiation , Delivery of Health Care , Humans , Neoplasms/drug therapy , Receptors, Retinoic Acid , Tretinoin/pharmacology , Vitamin A/pharmacology
5.
Biochim Biophys Acta Mol Cell Res ; 1869(1): 119142, 2022 01.
Article in English | MEDLINE | ID: mdl-34599982

ABSTRACT

Retinoic acid (RA) induces the differentiation of human promyelocytic leukemia HL60 cells into granulocytic cells and inhibits proliferation. Certain of actions of RA are mediated by RA nuclear receptors that regulate gene expression. However, it is also known that direct protein modification by RA (retinoylation) can occur. One such retinoylated protein in HL60 cells is a regulatory subunit of protein kinase A (PKA), which is increased in the nucleus following RA treatment and which then increases phosphorylation of other nuclear proteins. However, a complete understanding of which nuclear proteins are phosphorylated is lacking. In the current study, we employed mass spectrometry to identify one of the PKA-phosphorylated proteins as a serine/arginine-rich splicing factor 1 (SF2, SRSF1). We found that RA treatment increased the level of PKA-phosphorylated SF2 but decreased the level of SF2. While SF2 regulates myelogenous cell leukemia-1 (Mcl-1, anti-apoptotic factor), RA treatment reduced the level of Mcl-1L (full-length Mcl-1 long) and increased the level of Mcl-1S (Mcl-1 short; a short splicing variant of the Mcl-1). Furthermore, treatment with a PKA inhibitor reversed these effects on Mcl-1 and inhibited RA-induced cell differentiation. In contrast, treatment with a Mcl-1L inhibitor enhanced RA-induced cell differentiation. These results indicate that RA activates PKA in the nucleus, increases phosphorylation of SF2, raises levels of Mcl-1S and lowers levels of Mcl-1L, resulting in the induction of differentiation. RA-modified PKA may play an important role in inducing cell differentiation and suppressing cell proliferation.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , Serine-Arginine Splicing Factors/metabolism , Tretinoin/pharmacology , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Humans , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Phosphorylation , Protein Kinase Inhibitors/pharmacology
6.
Biochim Biophys Acta Mol Cell Res ; 1868(6): 118968, 2021 05.
Article in English | MEDLINE | ID: mdl-33454316

ABSTRACT

Retinoic acid (RA) induces granulocytic differentiation and inhibits the growth of human promyelocytic leukemia HL60 cells. α-Actinin-4 is a member of the α-actinin family, which exhibits unique mechanosensory regulation. Herein, we elucidated the effects of RA on α-actinin-4 expression during cell differentiation. RA increased the levels of α-actinin-4 protein significantly, while mRNA expression remained unchanged. In addition, RA treatment altered the intracellular localization of α-actinin-4 from the nucleus to the cytoplasm. Cells pretreated with RA, maintained α-actinin-4 protein levels after cycloheximide treatment as compared with control cells. The amount of ubiquitylated α-actinin-4 protein in RA-treated cells was less than in control cells. These results indicate that RA may inhibit nuclei transport and proteasomal degradation of α-actinin-4 protein. α-Actinin-4 may play a significant role in RA-induced differentiation, including the promotion of cytomorphology changes.


Subject(s)
Actinin/metabolism , Cycloheximide/pharmacology , Leukemia, Promyelocytic, Acute/metabolism , Tretinoin/pharmacology , Up-Regulation , Actinin/genetics , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Cytoplasm/metabolism , Gene Expression Regulation, Neoplastic/drug effects , HL-60 Cells , Humans , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/genetics , Proteolysis , Ubiquitination
7.
Biol Pharm Bull ; 43(7): 1081-1087, 2020 Jul 01.
Article in English | MEDLINE | ID: mdl-32295975

ABSTRACT

Vancomycin (VAN) is an anti-microbial agent used to treat a number of bacterial infections, which has a high incidence of nephrotoxicity. We examined the pharmacokinetics of VAN retrospectively based on trough concentrations at large scale and identified pharmacokinetic differences between Japanese patients having solid malignancy and non-malignancy patients. Data were analyzed from 162 solid malignancy patients and 261 non-malignancy patients, including the patient's background, VAN dose, and pharmacokinetics of VAN. We failed to detect differences in values for VAN clearance or shorter elimination half-lives between these two groups. In contrast, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to solid malignancies in each stage. We conclude that VAN clearance in solid malignancy patients is increased and that the blood concentration of VAN becomes lower than expected. These results suggest that early monitoring of VAN levels in solid malignancy patients might be essential for maintaining desired effects without side-effects.


Subject(s)
Anti-Bacterial Agents/blood , Drug Monitoring/methods , Neoplasms/blood , Vancomycin/blood , Aged , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Female , Humans , Male , Metabolic Clearance Rate/drug effects , Metabolic Clearance Rate/physiology , Middle Aged , Neoplasms/drug therapy , Retrospective Studies , Vancomycin/therapeutic use
8.
Biol Pharm Bull ; 42(12): 2089-2094, 2019 Dec 01.
Article in English | MEDLINE | ID: mdl-31534058

ABSTRACT

The pharmacokinetics of vancomycin (VAN) was retrospectively examined based on trough concentrations at large scale to identify pharmacokinetic differences between Japanese hematologic malignancy and non-malignancy patients. Data from 261 hematologic malignancy patients and 261 non-malignancy patients, including the patient's background, VAN dose, and pharmacokinetics of VAN estimated by an empirical Bayesian method, were collected and analyzed. Our results showed significantly higher values for VAN clearance and shorter elimination half-lives in patients with hematologic malignancies than non-malignancy patients. In addition, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to hematologic malignancies. In conclusion, since in hematologic cancer patients VAN clearance is increased, the blood concentration of VAN becomes lower than expected and this may contribute to the survival of resistant bacteria when VAN is administered at low doses. These results suggest that early monitoring of VAN levels in hematologic cancer patients might be recommended to maintain desired effects without side-effects.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Hematologic Neoplasms/drug therapy , Vancomycin/pharmacokinetics , Adult , Aged , Aged, 80 and over , Drug Monitoring , Female , Humans , Japan , Male , Metabolic Clearance Rate , Middle Aged , Retrospective Studies , Vancomycin/administration & dosage , Vancomycin/blood
9.
J Oleo Sci ; 68(8): 793-802, 2019 Aug 01.
Article in English | MEDLINE | ID: mdl-31292344

ABSTRACT

Atopic dermatitis (AD) is a cutaneous condition characterized by itchy, swollen, and dry skin, which is mediated by T helper cell-related cytokines. ß-Carotene, a natural red pigment found in plants, exhibits antioxidant activity that has been shown to promote an inflammatory response. Because it is not clear whether ß-carotene suppresses inflammation in AD skin tissues, we examined the effects of oral administration of ß-carotene in mice induced by a low zinc/magnesium diet (HR-AD diet). Our studies found that AD-like inflammation was remarkably reduced by ß-carotene. In addition, ß-carotene significantly suppressed protein expression of TNF-α, IL-1ß, and MCP-1 and mRNA expression of TSLP, IL-6, IL-1ß, IL-4, IL-5, and Par-2 in AD-like skin tissues. It was also found that mRNA and protein expression of filaggrin (a major structural protein in epidermis) in AD-like skin was significantly elevated by ß-carotene administration. Furthermore, ß-carotene treatment significantly reduced the activity and/or mRNA expression of matrix metalloproteinases (MMPs), degradation of the extracellular matrix and regulation of chemokines. These results suggest that ß-carotene reduces skin inflammation through the suppressed expression of inflammatory factors or the activity of MMPs as well as the promotion of filaggrin expression in AD-like skin. ß-Carotene is a potent anti-inflammatory agent, which improves AD-like skin by enhancing the skin barrier function.


Subject(s)
Dermatitis, Atopic/drug therapy , beta Carotene/therapeutic use , Administration, Oral , Animals , Cytokines/metabolism , Dermatitis, Atopic/pathology , Diet/adverse effects , Epidermis/pathology , Extracellular Matrix/metabolism , Filaggrin Proteins , Gene Expression/genetics , Inflammation/drug therapy , Intermediate Filament Proteins/metabolism , Male , Mice, Hairless , beta Carotene/administration & dosage
10.
Exp Dermatol ; 28(9): 1044-1050, 2019 09.
Article in English | MEDLINE | ID: mdl-31287602

ABSTRACT

Skin acts as a barrier, which protects internal tissues and promotes moisture retention. Atopic dermatitis (AD) is an inflammatory skin disease associated with a variety of genetic and environmental factors that involve helper T cells. ß-Carotene (provitamin A) exhibits antioxidant activity and activates the immune system. However, it is not clear whether inflammation in AD skin is improved by posttreatment with ß-carotene. In the current study, we investigated the effects of ß-carotene on the skin of hairless mice with oxazolone-induced inflammation/oedema (Ox-AD mice). We found that skin inflammation was significantly reduced by oral administration of ß-carotene. In addition, treatment with ß-carotene suppressed protein levels of TNF-α, IL-1ß and MCP-1, as well as mRNA expression associated with IL-1ß, IL-6, IL-4 and Par-2 in skin tissues. Furthermore, the mRNA and protein levels of filaggrin, a structural protein in the epidermal stratum corneum, were elevated by ß-carotene administration as compared with Ox-AD mice. ß-Carotene significantly reduced the activity of proMMP-9, but not proMMP-2. These results suggest that in Ox-AD mice, ß-carotene improves skin inflammation by suppressing the expression of inflammatory factors, promoting filaggrin expression and reducing MMP-9 activity. ß-Carotene is a potent anti-inflammatory agent that improves the barrier functions of AD skin.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Dermatitis, Atopic/drug therapy , Skin/drug effects , beta Carotene/therapeutic use , Administration, Oral , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/pharmacology , Cytokines/biosynthesis , Cytokines/genetics , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , Enzyme Precursors/biosynthesis , Filaggrin Proteins , Gene Expression Regulation/drug effects , Inflammation Mediators/metabolism , Intermediate Filament Proteins/biosynthesis , Intermediate Filament Proteins/genetics , Matrix Metalloproteinase 9/biosynthesis , Mice , Mice, Hairless , Oxazolone/toxicity , RNA, Messenger/biosynthesis , Skin/metabolism , Skin/pathology , Specific Pathogen-Free Organisms , beta Carotene/administration & dosage , beta Carotene/pharmacology
11.
Biol Pharm Bull ; 42(7): 1134-1139, 2019 Jul 01.
Article in English | MEDLINE | ID: mdl-30982786

ABSTRACT

Cancer is the leading cause of death and there is a particularly pressing need to develop effective treatments for breast and prostate cancer. In the current study, we show the inhibitory effects of cinnamic acid derivatives, including caffeic acid phenethyl ester (CAPE, 1), on the growth of breast and prostate cancer cells. Among the compounds examined, 3,4,5-trihydroxycinnamic acid decyl ester (6) showed the most potent inhibition of cancer cell growth by the induction of apoptosis. Compound 6 could be a new anti-cancer agent for use against breast and prostate cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Cinnamates/pharmacology , Prostatic Neoplasms/drug therapy , Cell Proliferation/drug effects , Humans , MCF-7 Cells , Male , PC-3 Cells
12.
Biochem Biophys Res Commun ; 495(1): 652-658, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29137983

ABSTRACT

Acetoacetyl-CoA synthetase (AACS) is the enzyme responsible for cholesterol and fatty acid synthesis in the cytosol. We have previously shown that AACS has an important role in normal neuronal development and that knockdown of SREBP-2, which orchestrates cholesterol synthesis, resulted in the downregulation of AACS mRNA levels. In this study, we investigated the transcriptional mechanism of AACS in Neuro-2a, neuroblastoma cells. Luciferase assay showed that the minimal core promoter of the mouse AACS gene is located in a region with 110 bps upstream from the transcription start site. Mutagenesis studies showed that the Sp1 binding site was crucial for AACS promoter activity. ChIP assay and DNA affinity precipitation assay showed that Sp1 binds to the Sp1 binding site on the promoter region of AACS. Moreover, overexpression of Sp1 increased AACS mRNA levels. Knockdown of AACS resulted in a decrease in histone deacetylase 9, associated with gene silencing. These results suggest that Sp1 regulates gene expression of AACS in Neuro-2a cells and ketone body utilization affects the balance of histone acetylation.


Subject(s)
Coenzyme A Ligases/genetics , Neuroblastoma/enzymology , Neuroblastoma/genetics , Sp1 Transcription Factor/genetics , Transcriptional Activation/genetics , Animals , Cell Line, Tumor , Coenzyme A Ligases/metabolism , Gene Expression Regulation, Enzymologic/genetics , Gene Expression Regulation, Neoplastic/genetics , Mice , Promoter Regions, Genetic/genetics , Sp1 Transcription Factor/metabolism
13.
Bioorg Med Chem Lett ; 27(20): 4664-4672, 2017 10 15.
Article in English | MEDLINE | ID: mdl-28927789

ABSTRACT

Neuroblastoma is an aggressive and drug-resistant refractory cancer. The human high-risk neuroblastoma cell line, SK-N-AS (non-amplified N-myc) is derived from stromal cells and it is resistant to treatment with retinoic acid (1, RA), which is a chemotherapeutic agent used to induce neuronal cellular differentiation of neuroblastomas. We have developed p-dodecylaminophenol (3, p-DDAP), based on N-(4-hydroxyphenyl)retinamide (2, 4-HPR), a synthetic amide of 1, since 1 and 2 are associated with the side-effect of nyctalopia. In order to evaluate the effects of 3 on high-risk neuroblastomas, we employed SK-N-AS cells as well asa second high-risk human neuroblastoma cell line, IMR-32, which is derived from neuronal cells (amplified N-myc, drug sensitive). Compound 3 suppressed cell growth of SK-N-AS and IMR-32 cells more effectively than 1, 2, p-decylaminophenol (4, p-DAP), N-(4-hydroxyphenyl)dodecananamide (5, 4-HPDD) or N-(4-hydroxyphenyl)decananamide (6, 4-HPD). In SK-N-AS cells, 3 induced G0/G1 arrest and apoptosis to a greater extent than 1 and 2. In IMR-32 cells, 3 induced apoptosis to a similar extent as 1 and 2, potentially by inhibiting N-myc expression. In addition, i.p. administration of 3 suppressed tumor growth in SK-N-AS-implanted mice in vivo. Since 3 showed no effects on blood retinol concentrations, in contrast to reductions following the administration of 2, it exhibited excellent anticancer efficacy against high-risk neuroblastoma SK-N-AS and IMR-32 expressing distinct levels of N-myc. Compound 3 may have potential for clinical use in the treatment of refractory neuroblastoma with reduced side effects.


Subject(s)
Aminophenols/chemistry , Aminophenols/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Aminophenols/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Caspase 3/metabolism , Cell Line, Tumor , G1 Phase Cell Cycle Checkpoints/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice , Mice, Nude , N-Myc Proto-Oncogene Protein/genetics , N-Myc Proto-Oncogene Protein/metabolism , Neuroblastoma/drug therapy , Neuroblastoma/metabolism , Neuroblastoma/pathology , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Transplantation, Heterologous
14.
Biol Pharm Bull ; 40(4): 486-494, 2017 Apr 01.
Article in English | MEDLINE | ID: mdl-28100867

ABSTRACT

Vitamin A is an essential nutrient that is obtained from the daily diet. The major forms of vitamin A in the body consist of retinol, retinal, retinoic acid (RA), and retinyl esters. Retinal is fundamental for vision and RA is used in clinical therapy of human acute promyelocytic leukemia. The actions of retinol and retinyl palmitate (RP) are not known well. Recently, we found that retinol is a potent anti-proliferative agent against human refractory cancers, including gallbladder cancer, being more effective than RA, while RP was inactive. In the current study, we determined serum retinol concentrations in xenograft mice bearing tumors derived from four refractory cancer cell lines. We also examined the effects of vitamin A on proliferation of human gallbladder cancer cells in vivo. Serum retinol concentrations were significantly lower in xenograft mice with tumors derived from various refractory cancer cell lines as compared with control mice. The growth of tumors was inhibited with increasing serum retinol concentrations obtained post-administration of RP. In addition, pre-administration of RP increased serum retinol concentrations and suppressed tumor growth. These results indicate that administration of RP can maintain retinol concentrations in the body and that this might suppress cancer cell growth and attachment. The regulation of vitamin A concentration in the body, which is critical biomarker of health, could be beneficial for cancer prevention and therapy.


Subject(s)
Carcinogenesis/drug effects , Drug Resistance, Neoplasm , Neoplasms/prevention & control , Vitamin A/therapeutic use , Vitamins/therapeutic use , Animals , Cell Line, Tumor , Diet, Healthy/methods , Diterpenes , Humans , Male , Mice , Mice, Nude , Neoplasms/drug therapy , Retinyl Esters , Specific Pathogen-Free Organisms , Tretinoin/pharmacology , Vitamin A/administration & dosage , Vitamin A/analogs & derivatives , Vitamin A/blood , Vitamin A/pharmacology , Vitamins/administration & dosage , Vitamins/blood , Xenograft Model Antitumor Assays
15.
Biol Pharm Bull ; 40(4): 495-503, 2017 Apr 01.
Article in English | MEDLINE | ID: mdl-28100868

ABSTRACT

Among the constituents of the essential nutrient vitamin A, retinol is a potent suppressor of refractory cancer cell growth linked to tumor progression, showing greater efficacy than retinoic acid (RA). However, the mechanisms of retinol action on human refractory cancer are not known well. In the current study, we examined the actions of retinol on proliferation of human gallbladder cancer NOZ C-1 cells. Retinol and RA inhibited the proliferation of human NOZ C-1 cells in dose-dependent manner, while RA was less potent than retinol. Cell incorporation of RA was approximately two-fold higher than retinol and was not correlated with anti-proliferative activity. Retinol did not affect caspase-3 activity or mRNA expression of Bax and Bcl-2, which are associated with apoptosis. In addition, protein expression of phosphorylated extracellular signal-regulated kinase (p-ERK)/ERK and p-Akt/Akt were not significantly changed by retinol treatment. In contrast, retinol treatment significantly increased the mRNA expression of endoplasmic reticulum (ER) stress factors (heme oxygenase 1 (HMOX1), CCAAT/enhancer-binding protein homologous protein (CHOP), 78 kDa glucose-regulated protein (GRP78), and DnaJ (Hsp40) homolog, subfamily B, member 9 (DNAJB9)). Furthermore, the number of cells in the G0/G1 phase was increased, while the number of cells in the S phase were decreased by retinol treatment. Retinol increased expression of the autophagy-associated protein, LC3-II. These results indicate that retinol is a potent suppressor of gallbladder cancer cell growth by mechanisms that involve ER stress, which results in autophagy and cell cycle delay. This suggests that retinol might be useful for anticancer prevention and therapy in the clinic.


Subject(s)
Autophagy/drug effects , Endoplasmic Reticulum Stress/drug effects , Tretinoin/pharmacology , Vitamin A/pharmacology , Vitamins/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Cycle Checkpoints , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm , Endoplasmic Reticulum Chaperone BiP , Extracellular Signal-Regulated MAP Kinases/metabolism , Gallbladder Neoplasms/drug therapy , Gallbladder Neoplasms/prevention & control , HSP40 Heat-Shock Proteins/metabolism , Heat-Shock Proteins/metabolism , Heme Oxygenase-1/metabolism , Humans , Membrane Proteins/metabolism , Microtubule-Associated Proteins/metabolism , Molecular Chaperones/metabolism , Phosphorylation , RNA, Messenger/metabolism , Transcription Factor CHOP/metabolism , Vitamin A/therapeutic use , Vitamins/therapeutic use
16.
Biochim Biophys Acta Gen Subj ; 1861(2): 276-285, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27913186

ABSTRACT

BACKGROUND: Activation of protein kinase A (PKA) occurs during retinoic acid (RA)-induced granulocytic differentiation of human promyelocytic leukemia HL60 cells. It is known that the RIIα regulatory subunit of PKA, is modified by RA (retinoylated) in the early stages of differentiation. We have investigated the effects of RA on PKA during cell differentiation in order to understand the potential significance of this process in the retinoylation of RIIα subunits. METHODS: Immunoblotting, immunoprecipitation, confocal microscopy, PCR, and PKA activity assays were employed for characterizing the effects of RA on PKA. RESULTS: We found that RA induces intracellular mobility of RIIα and the activation of PKA in HL60 cells. Increases in RIIα levels were observed in RA-treated HL60 cells. RA treatment altered intracellular localization of the PKA subunits, RIIα and Cα, and increased their protein levels in the nuclei as detected by both immunoblotting and immunostaining analyses. Coincident with the increase in nuclear Cα, RA-treated HL60 cells showed increases in both the protein phosphorylation activity of PKA and the levels of phosphorylated proteins in nuclear fractions as compared to control cells. In addition, RIIα protein was stabilized in RA-treated HL60 cells as compared to control cells. CONCLUSIONS: These results suggest that RA stabilizes RIIα protein and activates PKA in the nucleus, with a resultant increase in the phosphorylation of nuclear proteins. GENERAL SIGNIFICANCE: Our evidence suggests that retinoylation of PKA might contribute to its stabilization and activation and that this could potentially participate in RA's ability to induce granulocytic differentiation of HL60 cells.


Subject(s)
Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Tretinoin/pharmacology , Cell Differentiation/drug effects , Cell Line, Tumor , HL-60 Cells , Humans , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/metabolism , Neoplasm Proteins/metabolism , Nuclear Proteins/metabolism , Phosphorylation/drug effects , Protein Subunits/metabolism , Signal Transduction/drug effects
17.
Biochim Biophys Acta ; 1861(12 Pt A): 2011-2019, 2016 12.
Article in English | MEDLINE | ID: mdl-27720952

ABSTRACT

Retinoic acid (RA) has a variety of biological effects in mammalian cells and tissues. It is well known that RA induces differentiation of human acute promyelocytic leukemia (APL) HL60 cells, fresh human APL cells, and clinical remission in patients with APL. Retinoylation (acylation of proteins by RA) is a possible pathway for RA action. However, an understanding of the role that retinoylation plays in the actions of RA is lacking. In the current study, several retinoylated proteins were detected in RA-treated HL60 fractions following Mono Q anion exchange chromatography and analysis using two-dimensional polyacrylamide gel electrophoresis. One of the retinoylated proteins was identified as Rho-GDIß (28kDa) by TOF-MS and co-migration with Rho-GDIß (28kDa). Truncated Rho-GDIß (23kDa, N∆19), a product of cleavage by caspase-3, was not retinoylated. RA covalently bound to the Thr2 residue in Rho-GDIß (5kDa), which is the second product resulting from the cleavage of Rho-GDIß (28kDa) by caspase-3. RA treatment increased the level of Rho-GDIß (28kDa) and decreased the level of Rho-GDIß (23kDa). RA did not induce caspase-3 activity or Rho-GDIß mRNA expression. It is likely that retinoylation of Rho-GDIß increases its metabolic stability.


Subject(s)
Acylation/physiology , Leukemia, Myeloid/metabolism , Tretinoin/pharmacology , rho Guanine Nucleotide Dissociation Inhibitor beta/metabolism , Acylation/drug effects , Amino Acid Sequence , Caspase 3/metabolism , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Line, Tumor , HL-60 Cells , Humans , RNA/metabolism , RNA, Messenger/metabolism
18.
FEBS Lett ; 590(11): 1592-601, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27129883

ABSTRACT

Acetoacetyl-CoA synthetase (AACS) is a ketone body-utilizing enzyme and is responsible for the synthesis of cholesterol and fatty acids. We have previously shown that AACS is cleaved by legumain, a lysosomal asparaginyl endopeptidase. In this study, we attempted to determine the cleavage site of AACS. Mutagenesis analysis of AACS revealed that Asn547 is the specific cleavage site of AACS in mouse livers. The cleaved form of AACS (1-547) lost the ability to convert acetoacetate to acetoacetyl-CoA. Moreover, hydrodynamics-based gene transduction showed that overexpression of AACS (1-547) increases the protein expression of caveolin-1, the principal component of the caveolae. These results suggest that cleavage of AACS by legumain is critical for the regulation of enzymatic activity and results in gain-of-function changes.


Subject(s)
Coenzyme A Ligases/chemistry , Coenzyme A Ligases/metabolism , Cysteine Endopeptidases/metabolism , Animals , Binding Sites , Cells, Cultured , Enzyme Activation , HEK293 Cells , Humans , Male , Mice , Mice, Transgenic , Protein Interaction Domains and Motifs , Proteolysis , Substrate Specificity
19.
Biochem Biophys Res Commun ; 473(2): 654-61, 2016 Apr 29.
Article in English | MEDLINE | ID: mdl-27021680

ABSTRACT

Previous studies have shown that high-fat diet (HFD)-induced obesity increases the acetoacetyl-CoA synthetase (AACS) gene expression in lipogenic tissue. To investigate the effect of obesity on the AACS gene in other tissues, we examined the alteration of AACS mRNA levels in HFD-fed mice. In situ hybridization revealed that AACS was observed in several regions of the embryo, including the backbone region (especially in the somite), and in the epiphysis of the adult femur. AACS mRNA expression in the adult femur was higher in HFD-fed mice than in normal-diet fed mice, but this increase was not observed in high sucrose diet (HSD)-induced obese mice. In addition, HFD-specific increases were observed in the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and interleukin (IL)-6 genes. Moreover, we detected higher AACS mRNA expression in the differentiated osteoclast cells (RAW 264), and found that AACS mRNA expression was significantly up-regulated by IL-6 treatment only in osteoclasts. These results indicate the novel function of the ketone body in bone metabolism. Because the abnormal activation of osteoclasts by IL-6 induces bone resorption, our data suggest that AACS and ketone bodies are important factors in the relationship between obesity and osteoporosis.


Subject(s)
Bone and Bones/pathology , Diet, High-Fat/adverse effects , Ketone Bodies/metabolism , Obesity/etiology , Obesity/metabolism , Osteoclasts/pathology , Animals , Bone and Bones/metabolism , Cell Line , Coenzyme A Ligases/genetics , Inflammation/etiology , Inflammation/genetics , Inflammation/metabolism , Interleukin-6/genetics , Ketone Bodies/genetics , Male , Mice , Mice, Obese , Obesity/genetics , Osteoclasts/metabolism , RNA, Messenger/genetics , Up-Regulation
20.
Biol Pharm Bull ; 39(4): 636-40, 2016.
Article in English | MEDLINE | ID: mdl-26822412

ABSTRACT

Vitamin A constituents include retinal, which plays a role in vision, and retinoic acid (RA), which has been used in the therapy of human acute promyelocytic leukemia. However, the effects on cancer of retinol (Rol) and its ester, retinyl palmitate (RP) are not known well. In the current study, we examined the effects of these agents on proliferation and adhesion of various cancer cells. Rol exhibited dose-dependent inhibition of the proliferation of human refractory and prostate cancer cells, while RA and RP showed little or no effect. In contrast, RA inhibited the growth of human breast cancer cells to a greater extent than Rol at low concentrations, but not at high concentrations. Rol suppressed adhesion of refractory and prostate cancer cells to a greater extent than RA, while it suppressed adhesion of breast cancer cells as well as RA and of JHP-1 cells less effectively than RA. These results indicate that Rol is a potent suppressor of cancer cell growth and adhesion, which are both linked to metastasis and tumor progression. Rol might be useful for the clinical treatment of cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Tretinoin/pharmacology , Vitamin A/analogs & derivatives , Vitamin A/pharmacology , Cell Adhesion/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Diterpenes , Drug Resistance, Neoplasm/drug effects , Humans , Neoplasms/drug therapy , Retinyl Esters
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