|
1
|
Yamada K, Yoshida K. Multiple subcellular localizations and functions of protein kinase Cδ in liver cancer. World J Gastroenterol 2022; 28:188-198. [PMID: 35110944 PMCID: PMC8776529 DOI: 10.3748/wjg.v28.i2.188] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 06/25/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Protein kinase Cδ (PKCδ) is a member of the PKC family, and its implications have been reported in various biological and cancerous processes, including cell proliferation, cell death, tumor suppression, and tumor progression. In liver cancer cells, accumulating reports show the bi-functional regulation of PKCδ in cell death and survival. PKCδ function is defined by various factors, such as phosphorylation, catalytic domain cleavage, and subcellular localization. PKCδ has multiple intracellular distribution patterns, ranging from the cytosol to the nucleus. We recently found a unique extracellular localization of PKCδ in liver cancer and its growth factor-like function in liver cancer cells. In this review, we first discuss the structural features of PKCδ and then focus on the functional diversity of PKCδ based on its subcellular localization, such as the nucleus, cell surface, and extracellular space. These findings improve our knowledge of PKCδ involvement in the progression of liver cancer.
Collapse
Affiliation(s)
- Kohji Yamada
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Kiyotsugu Yoshida
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| |
Collapse
|
|
2
|
Liu L, Shen YF, Hu Y, Lu JF. Antiviral effect of 7-(4-benzimidazole-butoxy)-coumarin on rhabdoviral clearance via Nrf2 activation regulated by PKCα/β phosphorylation. FISH & SHELLFISH IMMUNOLOGY 2018; 83:386-396. [PMID: 30243774 DOI: 10.1016/j.fsi.2018.09.054] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 09/17/2018] [Accepted: 09/19/2018] [Indexed: 06/08/2023]
Abstract
Coumarin forms an elite class of naturally occurring compounds that possess promising antiviral therapeutic perspectives. In the previous study, we designed and synthesized a coumarin derivative, 7-(4-benzimidazole-butoxy)-coumarin (BBC), to evaluate its antiviral activity on spring viraemia of carp virus (SVCV). In this study, our results show that BBC does not affect viral adhesion and delivery from endosomes to the cytosol, indicating BBC has no inhibitory activity in the early stage of viral infection. Further data are determined that BBC significantly declines SVCV-infected apoptosis and recovers caspase-3/8/9 activity. To reveal the pathway that affects Nrf2 translocation by BBC, we examine changes in protein kinase C (PKC) in EPC cells treated with BBC. We observe that BBC results in a higher phosphorylation of PKCα/β that is involved in the activation of erythroid 2-related factor 2 (Nrf2) phosphorylation to favor Nrf2 translocation to nucleus at 24 and 48 h. In addition, the results show that BBC also up-regulates both antiviral responses, heme oxygenase-1 (HO-1) expression and cellular IFN response. Overall, this mechanism of action provides a new therapeutic target for the treatment of SVCV infection, and these results suggest that treatment with BBC is effective in reducing SVCV infection and differently regulates SVCV-induced undesirable conditions.
Collapse
Affiliation(s)
- Lei Liu
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China.
| | - Yu-Feng Shen
- College of Animal Science and Technology, Northwest A&F University, Xinong Road 22nd, Yangling, Shaanxi, 712100, China
| | - Yang Hu
- College of Animal Science and Technology, Northwest A&F University, Xinong Road 22nd, Yangling, Shaanxi, 712100, China
| | - Jian-Fei Lu
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China
| |
Collapse
|
|
3
|
Omar HA, Zaher DM, Srinivasulu V, Hersi F, Tarazi H, Al-Tel TH. Design, synthesis and biological evaluation of new pyrrolidine carboxamide analogues as potential chemotherapeutic agents for hepatocellular carcinoma. Eur J Med Chem 2017; 139:804-814. [PMID: 28865276 DOI: 10.1016/j.ejmech.2017.08.054] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Revised: 08/22/2017] [Accepted: 08/23/2017] [Indexed: 12/16/2022]
Abstract
The successful targeting of different malignancies by OSU-2S, encouraged us to design and synthesize a novel series of pyrrolidine aryl carboxamide derivatives. In this context, we found that, the amide nature and tether length were found to be key determinant elements for the anticancer activity of these new and rigid analogues of OSU-2S. The most effective analogues induced apoptosis in cancer cells by a similar mechanism to that of OSU-2S, possibly via the activation of PKCδ in addition to their ability to induce cell cycle arrest and inhibition of cancer cell migration. Compound 10m, possesses anticancer potency comparable to that of OSU-2S when tested against cancer cell lines under study, and was found to be safer on normal cells. Furthermore, compound 10m, was found to be about 2-folds more potent than the anticancer drug Sorafenib in hepatocellular carcinoma (HCC). The newly developed compounds represent a therapeutically promising approach for the treatment of HCC.
Collapse
Affiliation(s)
- Hany A Omar
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Dana M Zaher
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Vunnam Srinivasulu
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Fatema Hersi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Hamadeh Tarazi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Taleb H Al-Tel
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates.
| |
Collapse
|
|
4
|
Li H, Wang Y, Liu H, Shi Q, Li H, Wu W, Zhu D, Amos CI, Fang S, Lee JE, Li Y, Han J, Wei Q. Genetic variants of PDGF signaling pathway genes predict cutaneous melanoma survival. Oncotarget 2017; 8:74595-74606. [PMID: 29088810 PMCID: PMC5650365 DOI: 10.18632/oncotarget.20245] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 07/24/2017] [Indexed: 11/29/2022] Open
Abstract
To investigate whether genetic variants of platelet-derived growth factor (PDGF) signaling pathway genes are associated with survival of cutaneous melanoma (CM) patients, we assessed associations of single-nucleotide polymorphisms in PDGF pathway with melanoma-specific survival in 858 CM patients of M.D. Anderson Cancer Center (MDACC). Additional data of 409 cases from Harvard University were also included for further analysis. We identified 13 SNPs in four genes (COL6A3, NCK2, COL5A1 and PRKCD) with a nominal P < 0.05 and false discovery rate (FDR) < 0.2 in MDACC dataset. Based on linkage disequilibrium, functional prediction and minor allele frequency, a representative SNP in each gene was selected. In the meta-analysis using MDACC and Harvard datasets, there were two SNPs associated with poor survival of CM patients: rs6707820 C>T in NCK2 (HR = 1.87, 95% CI = 1.35-2.59, Pmeta= 1.53E-5); and rs2306574 T>C in PRKCD (HR = 1.73, 95% CI = 1.33-2.24, Pmeta= 4.56E-6). Moreover, CM patients in MDACC with combined risk genotypes of these two loci had markedly poorer survival (HR = 2.47, 95% CI = 1.58-3.84, P < 0.001). Genetic variants of rs6707820 C>T in NCK2 and rs2306574 T>C in PRKCD of the PDGF signaling pathway may be biomarkers for melanoma survival.
Collapse
Affiliation(s)
- Hong Li
- Department of Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, China.,Duke Cancer Institute, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.,Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Yanru Wang
- Duke Cancer Institute, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.,Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Hongliang Liu
- Duke Cancer Institute, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.,Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Qiong Shi
- Duke Cancer Institute, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.,Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Hongyu Li
- Duke Cancer Institute, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.,Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Wenting Wu
- Department of Epidemiology, Fairbanks School of Public Health, Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA
| | - Dakai Zhu
- Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA
| | - Christopher I Amos
- Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA
| | - Shenying Fang
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Jeffrey E Lee
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Yi Li
- Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jiali Han
- Department of Epidemiology, Fairbanks School of Public Health, Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA
| | - Qingyi Wei
- Duke Cancer Institute, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.,Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.,Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
| |
Collapse
|
|
5
|
A novel class I HDAC inhibitor, MPT0G030, induces cell apoptosis and differentiation in human colorectal cancer cells via HDAC1/PKCδ and E-cadherin. Oncotarget 2015; 5:5651-62. [PMID: 25015091 PMCID: PMC4170623 DOI: 10.18632/oncotarget.2155] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Accumulation of genetic and epigenetic changes contributes to cancer development and progression. Compared with gene mutations or deletions, epigenetic changes are reversible, which alter the chromatin structure remodeling instead of changes in DNA sequence, and therefore become a promising strategy for chemotherapy. Histone deacetylases (HDACs) are a class of enzymes that responsible for the epigenetic regulation of gene expression. MPT0G030 is a potent and selective class I HDAC inhibitor which showed broad-spectrum cytotoxicity against various human cancer cell lines. in vitro fluorometric HDAC activity assay showed that MPT0G030 effectively inhibited Class I HDACs (HDAC1~3), which were overexpressed in many malignant neoplasms. Interestingly, MPT0G030 not only induced histone acetylation and tumor suppressor p21 transcription, but also redistributed E-cadherin and activated Protein Kinase C δ (PKCδ), which was linked to cell apoptosis and differentiation. Further, activation of PKCδ was demonstrated to be modulated through HDAC1. The in vivo anticancer activity of MPT0G030 and the importance of PKCδ were confirmed in the HT-29 tumor xenograft models. Taken together, those results indicate that MPT0G030, a class I HDAC inhibitor, has great potential as a new drug candidate for cancer therapy.
Collapse
|
|
6
|
MARCKS protein mediates hydrogen peroxide regulation of endothelial permeability. Proc Natl Acad Sci U S A 2012; 109:14864-9. [PMID: 22927426 DOI: 10.1073/pnas.1204974109] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Impairment of endothelial barrier function is implicated in many vascular and inflammatory disorders. One prevalent mechanism of endothelial dysfunction is an increase in reactive oxygen species under oxidative stress. Previous reports have demonstrated that hydrogen peroxide (H(2)O(2)), a highly stable reactive oxygen species that modulates physiological signaling pathways, also enhances endothelial permeability, but the mechanism of this effect is unknown. Here, we identify the actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) as a key mediator of the H(2)O(2)-induced permeability change in bovine aortic endothelial cells. MARCKS knockdown and H(2)O(2) treatment alter the architecture of the actin cytoskeleton in endothelial cells, and H(2)O(2) induces the phosphorylation and translocation of MARCKS from the cell membrane to the cytosol. Using pharmacological inhibitors and small interference RNA constructs directed against specific proteins, we uncover a signaling cascade from Rac1 to Abl1, phospholipase Cγ1, and PKCδ that is triggered by H(2)O(2) and leads to MARCKS phosphorylation. Our findings establish a distinct role for MARCKS in the regulation of H(2)O(2)-induced permeability change in endothelial cells, and suggest potential new therapeutic targets for the treatment of disorders involving oxidative stress and altered endothelial permeability.
Collapse
|
|
7
|
Jiang W, Bian L, Ma LJ, Tang RZ, Xun S, He YW. Hyperthermia-induced apoptosis in Tca8113 cells is inhibited by heat shock protein 27 through blocking phospholipid scramblase 3 phosphorylation. Int J Hyperthermia 2011; 26:523-37. [PMID: 20569108 DOI: 10.3109/02656731003793393] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
PURPOSE Hyperthermia induces tumour cell apoptosis through the mitochondrial apoptotic pathway; however, the signal transduction mechanism underlying this process still needs to be fully elucidated. Phospholipid scramblase 3 (PLS3), a target of protein kinase C-delta (PKC-delta), resides in mitochondria and plays pivotal roles in regulating apoptotic response. Activated PLS3 facilitates cardiolipin (CL) translocation from the mitochondrial inner membrane to the outer leaflet of the mitochondrial outer membrane and triggers apoptosis. MATERIALS AND METHODS The tongue squamous cell carcinoma Tca8113 cells were transfected or co-transfected using Lipofectamine 2000 with plasmids pCMV-6xHis-PLS3, pCMV-6xHis-PLS3 (T21A), pHA-PKC-delta, pHA-PKC-delta-KD (K376R), pHA-Hsp27, and empty control plasmid pcDNA3.1. The transfected cells were heated in water bath at 43 degrees C for 20 min, 40 min and 60 min. Assessments of apoptosis and redistribution of mitochondrial cardiolipin were performed by flow cytometry. PLS3, PKC-delta, Hsp27, phosphorylation of PLS3 and PLS3/PKC-delta interaction were detected by western blotting. RESULTS In our study the results show that elevated levels of the wild-type PLS3, but not the PLS3 (T21A) mutant, is able to increase hyperthermia-induced CL translocation and apoptosis. Wild-type PKC-delta facilitates PLS3 phosphorylation, PKC-delta/PLS3 interaction, and CL translocation, which consequently promote apoptosis. In contrast, heat shock protein 27 (Hsp27) blocks PKC-delta-induced PLS3 phosphorylation, suppresses PKC-delta/PLS3 interaction and CL translocation, and inhibits apoptosis. CONCLUSIONS Our findings suggest that phosphorylation of PLS3 by PKC-delta is involved in the hyperthermia-induced apoptotic signal transduction pathway in Tca8113 cells, and that Hsp27 blocks this pathway to suppress hyperthermia-induced apoptosis.
Collapse
Affiliation(s)
- Wen Jiang
- The Affiliated Stomatological Hospital of Kunming Medical College, Kunming, China
| | | | | | | | | | | |
Collapse
|
|
8
|
Basu A, Sridharan S, Persaud S. Regulation of protein kinase C delta downregulation by protein kinase C epsilon and mammalian target of rapamycin complex 2. Cell Signal 2009; 21:1680-5. [PMID: 19632318 PMCID: PMC2748237 DOI: 10.1016/j.cellsig.2009.07.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2009] [Accepted: 07/13/2009] [Indexed: 11/12/2022]
Abstract
Phosphorylation and dephosphorylation of PKCs can regulate their activity, stability and function. We have previously shown that downregulation of PKC delta by tumor promoting phorbol esters was compromised when HeLa cells acquired resistance to cisplatin (HeLa/CP). In the present study, we have used these cells to understand the mechanism of PKC delta downregulation. A brief treatment of HeLa cells with phorbol 12,13-dibutyrate (PDBu) induced phosphorylation of PKC delta at the activation loop (Thr505), turn motif (Ser643), hydrophobic motif (Ser662) and Tyr-311 sites to a greater extent in HeLa/CP cells compared to HeLa cells. Prolonged treatment with PDBu led to downregulation of PKC delta in HeLa but not in HeLa/CP cells. The PKC inhibitor Gö 6983 inhibited PDBu-induced downregulation of PKC delta, decreased Thr505 phosphorylation and increased PKC delta tyrosine phosphorylation at Tyr-311 site. However, knockdown of c-Abl, c-Src, Fyn and Lyn had little effect on PKC delta downregulation and Tyr311 phosphorylation. Pretreatment with the phosphatidylinositol 3-kinase inhibitor Ly294002 and mTOR inhibitor rapamycin restored the ability of PDBu to downregulate PKC delta in HeLa/CP cells. Knockdown of mTOR and rictor but not raptor facilitated PKC delta downregulation. Depletion of PKC epsilon also enhanced PKC delta downregulation by PDBu. These results suggest that downregulation of PKC delta is regulated by PKC epsilon and mammalian target of rapamycin complex 2 (mTORC2).
Collapse
Affiliation(s)
- Alakananda Basu
- Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
| | | | | |
Collapse
|
|
9
|
Blumberg PM, Kedei N, Lewin NE, Yang D, Czifra G, Pu Y, Peach ML, Marquez VE. Wealth of opportunity - the C1 domain as a target for drug development. Curr Drug Targets 2008; 9:641-52. [PMID: 18691011 PMCID: PMC3420355 DOI: 10.2174/138945008785132376] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The diacylglycerol-responsive C1 domains of protein kinase C and of the related classes of signaling proteins represent highly attractive targets for drug development. The signaling functions that are regulated by C1 domains are central to cellular control, thereby impacting many pathological conditions. Our understanding of the diacylglycerol signaling pathways provides great confidence in the utility of intervention in these pathways for treatment of cancer and other conditions. Multiple compounds directed at these signaling proteins, including compounds directed at the C1 domains, are currently in clinical trials, providing strong validation for these targets. Extensive understanding of the structure and function of C1 domains, coupled with detailed insights into the molecular details of ligand - C1 domain interactions, provides a solid basis for rational and semi-rational drug design. Finally, the complexity of the factors contributing to ligand - C1 domain interactions affords abundant opportunities for manipulation of selectivity; indeed, substantially selective compounds have already been identified.
Collapse
Affiliation(s)
- P M Blumberg
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Center, Bethesda, MD 20892, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Shinmura K, Nagai M, Tamaki K, Bolli R. Loss of ischaemic preconditioning in ovariectomized rat hearts: possible involvement of impaired protein kinase C epsilon phosphorylation. Cardiovasc Res 2008; 79:387-94. [PMID: 18390563 PMCID: PMC2492728 DOI: 10.1093/cvr/cvn086] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Aims The aims of this study were to determine whether chronic oestrogen withdrawal influences the development of ischaemic preconditioning (IPC) in female hearts, to investigate the mechanism whereby IPC is impaired, and to assess whether direct activation of protein kinase C (PKC) can mimic IPC in female hearts with chronic oestrogen depletion. Methods and results We performed Sham-operation (Sham) or bilateral ovariectomy on 16-week-old Sprague–Dawley female rats. Ovariectomized rats were randomized to subcutaneous implantation of 17β-estradiol (OxE) or placebo (OxP) pellets. Four weeks later, isolated, perfused hearts were subjected to 30 min of ischaemia followed by 120 min of reperfusion with or without three cycles of 5 min ischaemia/5 min reperfusion. The cardioprotective effect of IPC was completely lost in the OxP group. Western immunoblots revealed that in the OxP group, IPC failed to translocate PKCε to the membranous fraction and that phosphorylation of PKCε (Ser729) and phosphoinositide-dependent kinase (PDK) 1 (Ser241) was impaired. Oestrogen replacement restored the IPC effect, the translocation and phosphorylation of PKCε, and the phosphorylation of PDK1. In the OxP group, pre-treatment with a PKCε selective activator peptide (Ψ–εRACK) mimicked the IPC effect. Pre-treatment with a phosphatidylinositol-3 kinase inhibitor before IPC abrogated the translocation and phosphorylation of PKCε in the Sham group. Conclusions The cardioprotective effect of IPC is lost in female hearts with chronic oestrogen withdrawal and this is due, at least in part, to impaired translocation and phosphorylation of PKCε. Selective activation of PKCε-mediated signalling can fully restore the IPC effect in a manner analogous to oestrogen replacement.
Collapse
Affiliation(s)
- Ken Shinmura
- Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
| | | | | | | |
Collapse
|
|
11
|
Kim BC, Jeon WK, Hong HY, Jeon KB, Hahn JH, Kim YM, Numazawa S, Yosida T, Park EH, Lim CJ. The anti-inflammatory activity of Phellinus linteus (Berk. & M.A. Curt.) is mediated through the PKCdelta/Nrf2/ARE signaling to up-regulation of heme oxygenase-1. JOURNAL OF ETHNOPHARMACOLOGY 2007; 113:240-7. [PMID: 17644290 DOI: 10.1016/j.jep.2007.05.032] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2006] [Revised: 04/26/2007] [Accepted: 05/29/2007] [Indexed: 05/16/2023]
Abstract
It has been reported that heme oxygenase-1 (HO-1) mediates the anti-inflammatory activity of the n-BuOH subfraction (PL) prepared from fruiting bodies of Phellinus linteus. This continuing work aimed to elucidate the signaling pathway to the up-regulation of HO-1 by PL. In RAW264.7 macrophage cells, PL was able to enhance phosphorylation of protein kinase Cdelta (PKCdelta), but not PKCalpha/betaII, in a time-dependent manner. PL-induced HO-1 expression was dramatically released by GF109203X, a general inhibitor of PKC, and rottlerin, a specific PKCdelta inhibitor but not by Gö6976, a selective inhibitor for PKCalpha/beta. Additionally, PL treatment resulted in a marked increase in antioxidant response element (ARE)-driven transcriptional activity, which was dependent on PKCdelta but not PKCalpha. An increase by PL treatment in the ARE-driven transcriptional activity was further enhanced by Nrf2, whereas it was diminished by Keap1. Furthermore, pretreatment of rottlerin and overexpression of PKCdelta (K376R), a kinase-inactive form of PKCdelta, partly blocked the suppression by PL of nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression, and iNOS promoter activity, which were elevated in the lypopolysaccharide (LPS)-activated macrophages. Similarly, expression of matrix metalloproteinase-9 (MMP-9) and its promoter activity were suppressed by PL, which were dependent upon PKCdelta. The present findings indicate that Phellinus linteus gives rise to an anti-inflammatory activity though the PKCdelta/Nrf2/ARE signaling to the up-regulation of HO-1 in an in vitro inflammation model.
Collapse
Affiliation(s)
- Byung-Chul Kim
- Division of Life Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
| | | | | | | | | | | | | | | | | | | |
Collapse
|