Role of ellagic acid in regulation of apoptosis by modulating novel and atypical PKC in lymphoma bearing mice

BMC Complementary and Alternative Medicine

Manjula Vinayak¹  Sudha Mishra¹ 

[1] Biochemistry & Molecular Biology Laboratory, Centre of Advanced Study in Zoology, Banaras Hindu University, Varanasi 221005, India

关键词: Anaerobic glycolysis;    LDH-A;    Apoptosis;    PKC isozymes;   

Others  :  1222534
DOI  :  10.1186/s12906-015-0810-5

 received in 2015-01-05, accepted in 2015-08-07,  发布年份 2015

【 摘 要 】

Background

Protein kinase C regulates various cellular processes including cell proliferation, cell adhesion, apoptosis, angiogenesis, invasion, and metastasis. Activation of different PKC isozymes results in distinct cellular responses. Novel PKCs are mainly involved in apoptotic process. Atypical PKC subfamily plays a critical role in cell proliferation and apoptosis, cell differentiation and motility. However, Atypical PKCs show contradictory regulation in different tissues or cancer cells. The mechanism of diversified effects is not well explored. Antioxidant ellagic acid shows hepatoprotective, anti-carcinogenic and anti-mutagenic properties. Present study is focused to analyze the effect of ellagic acid on novel and atypical isozymes of PKC in regulation of PKC-mediated apoptosis in liver of lymphoma bearing mice. Implication of ellagic acid treatment to DL mice was analyzed on caspase-3 mediated apoptosis via PKCδ induced activation; and on maintenance of adequate supply of energy during cancer growth.

Methods

15–20 weeks old adult DL mice were divided into four groups (n = 6). Group 2, 3, 4 were treated with different doses of ellagic acid (40 mg/kg, 60 mg/kg and 80 mg/kg bw). The mice were sacrificed after 19 days of treatment and liver was used for study. The effect of ellagic acid was determined on expression of novel and atypical PKC isozymes. Apoptotic potentiality of ellagic acid was checked on activities of caspase-3 and PKCδ in terms of their catalytic fragments. Aerobic glycolysis was monitored by LDH activity, especially activity of LDH A.

Results

Ellagic acid treatment caused up regulation of expression of almost all novel and atypical PKC isozymes. Activities of PKCδ and caspase-3 were enhanced by ellagic acid, however activities of total LDH and LDH-A were inhibited.

Conclusion

The results show that ellagic acid promotes apoptosis in lymphoma bearing mice via novel and atypical PKCs which involves PKCδ induced caspase-3 activation; and inhibition of glycolytic pathway.

【 授权许可】

   
2015 Mishra and Vinayak.

【 图 表 】

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【 参考文献 】

• [1]Haughian JM, Jackson TA, Koterwas DM, Bradford AP. Endometrial cancer cell survival and apoptosis is regulated by protein kinase C alpha and delta. Endocr Relat Cancer. 2006; 13:1251-1267.
• [2]Ruvolo VR, Karanjeet KB, Schuster TF, Brown R, Deng Y, Hinchcliffe E et al.. Role for PKC δ in fenretinide-mediated apoptosis in lymphoid leukemia cells. J Signal Transduct. 2010; 2010:1-15.
• [3]Limesand KH, Schneider JC, Nakayama KI, Anderson SM, Reyland ME. Suppression of apoptosis in the protein kinase Cδ null mouse in vivo. J Biol Chem. 2006; 281:9728-9737.
• [4]Mishra S, Vinayak M. Ellagic acid checks lymphoma promotion via regulation of PKC signaling pathway. Mol Biol Rep. 2013; 40:1417-1428.
• [5]Jackson DN, Foster DA. The enigmatic protein kinase c delta: complex roles in cell proliferation and survival. FASEB J. 2004; 18:627-636.
• [6]Humphries MJ, Limesand KH, Schneider JC, Nakayama KI, Anderson SM, Reyland ME. Suppression of apoptosis in the protein kinase Cδ null mouse in vivo. J Biol Chem. 2006; 281:9728-9737.
• [7]Cataldi A, Di Giacomo R, Zara V, Rana MS. Ionizing radiation induces apoptotic signal through protein kinase delta and survival signal through Akt and Cyclic-nucleotide Response Element-binding Protein (CREB) in jurkat T cells. Biol Bull. 2009; 217:202-212.
• [8]Ohba M, Ishino K, Kashiwagi M, Kawabe S, Chida K, Huh NH et al.. Induction of differentiation in normal human keratinocytes by adenovirus mediated introduction of the eta and delta isoforms of protein kinase C. Mol Cell Biol. 1998; 18:5199-5207.
• [9]Sanz-Navares E, Fernandez N, Kazanietz MG, Rotenberg SA. Atypical protein kinase C zeta suppresses migration of mouse melanoma cells. Cell Growth Differ. 2001; 12:517-524.
• [10]Zhang L, Huang J, Yang N, Liang S, Barchetti A, Giannakakis A et al.. Integrative genomic analysis of protein kinase C (PKC) family identifies PKC iota as a biomarker and potential oncogene in ovarian carcinoma. Cancer Res. 2006; 66:4627-4635.
• [11]Pathak C, Jaiswal YK, Vinayak M. Queuine promotes antioxidant defence system by activating cellular antioxidant enzyme activities in cancer. Biosci Rep. 2008; 28:73-81.
• [12]Kivinena K, Kallajokia M, Taimena P. Caspase-3 is required in the apoptotic disintegration of the nuclear matrix. Exp Cell Res. 2005; 311:62-73.
• [13]Kanthasamy AG, Kitazawa M, Yang Y, Anantharam V, Kanthasamy A. Environmental neurotoxin dieldrin induces apoptosis via caspase-3 dependent proteolytic activation of protein kinase C delta: Implications for neurodegeneration in Parkinson’s disease. Mol Brain. 2008; 1:12. BioMed Central Full Text
• [14]Brodie C, Blumberg PM. Regulation of cell apoptosis by protein kinase c δ. Apoptosis. 2003; 8:19-27.
• [15]Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646-674.
• [16]Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA et al.. c-Myc transactivation of LDH-a: implications for tumor metabolism and growth. Proc Natl Acad Sci. 1997; 94:6658-6663.
• [17]Fjaeraa C, Nanberg E. Effect of ellagic acid on proliferation, cell adhesion and apoptosis in SH-SY5Y human neuroblastoma cells. Biomed Pharmacother. 2009; 63:254-261.
• [18]Losso JN, Bansode RR, Trappey A, Bawadi HA, Truax R. In vitro anti-proliferative activities of ellagic acid. J Nutr Biochem. 2004; 15:672-678.
• [19]Mishra S, Vinayak M. Anti-carcinogenic action of ellagic acid mediated via modulation of oxidative stress regulated genes in Dalton lymphoma bearing mice. Leuk Lymphoma. 2011; 52:2155-216.
• [20]Schwartz MK, Bodansky O. Lactic dehydrogenase (Clinical aspects). Methods Enzymol. 1966; 9:294-302.
• [21]Pathak C, Vinayak M. Modulation of lactate dehydrogenase isozymes by modified base queuine. Mol Biol Rep. 2005; 32:191-196.
• [22]Birt DB, Hendrich S, Wang W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther. 2001; 90:157-177.
• [23]Hung JH, Lu YS, Wang YC, Ma YH, Wang DS, Kulp SK et al.. FTY720 induces apoptosis in hepatocellular carcinoma cells through activation of protein kinase C delta signaling. Cancer Res. 2008; 68:1204-1212.
• [24]Vargo MA, Voss OH, Poustka F, Cardounel AJ, Grotewold E, Doseff AI. Apigenin-induced-apoptosis is mediated by the activation of PKC delta and caspases in leukemia cells. Biochem Pharmacol. 2006; 72:681-692.
• [25]Powell TC, Yin L. Over expression of PKC epsilon sensitizes LNCaP human prostate cancer cells to induction of apoptosis by bryostatin. Int J Cancer. 2006; 118:1572-1576.
• [26]Ishidaa M, Itsukaichi T, Daisuke K, Kikuchia H. Alteration of the PKCθ-Vav1 complex and phosphorylation of Vav1 in TCDD-induced apoptosis in the lymphoblastic T cell line, L-MAT. Toxicology. 2010; 275:72-78.
• [27]Schultz A, Jonsson JI, Larsson C. The regulatory domain of protein kinase Cθ localises to the Golgi complex and induces apoptosis in neuroblastoma and Jurkat cells. Cell Death Differ. 2003; 10:662-675.
• [28]Lu HC, Chou FP, Yeh KT, Chang YS, Hsu NC, Chang JG. Analysing the expression of protein kinase C eta in human hepatocellular carcinoma. Pathology. 2009; 41:626-629.
• [29]Zhao M, Xia L, Chen GO. Protein kinase Cd in apoptosis: a brief overview. Arch Immunol Ther Exp (Warsz). 2012; 60:361-372.
• [30]Oh JI, Chun KH, Joo SH, Oh YT, Lee SK. Caspase-3-dependent protein kinase C delta activity is required for the progression of Ginsenoside-Rh2 induced apoptosis in SK-HEP-1 cells. Cancer Lett. 2005; 230:228-238.
• [31]Lan Q, Morton LM, Armstrong B, Hartge P, Menashe I, Zheng T. Genetic variation in caspase genes and risk of non-Hodgkin lymphoma: a pooled analysis of 3 population-based case–control studies. Blood. 2009; 114:264-267.
• [32]Devarajan E, Sahin AA, Chen JS. Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. Oncogene. 2002; 21:8843-8851.
• [33]Voss OH, Kim S, Wewers MD, Dose AI. Regulation of monocyte apoptosis by the protein kinase C_-dependent phosphorylation of caspase-3. J Biol Chem. 2005; 280:17371-17379.
• [34]Xin M, Gao F, May WS, Flagg T, Deng X. Protein Kinase Cζ abrogates the pro apoptotic function of bax through phosphorylation. J Biol Chem. 2007; 282:21268-21277.
• [35]Nazarenko I, Jenny MKJ, Gieseler CWK, Sehouli J, Legewie S, Herbst L et al.. Atypical protein kinase c zeta exhibits a pro apoptotic function. Mol Cancer Res. 2010; 8:919-934.
• [36]Galvez AS, Duran A, Linares JF, Pathrose P, Castilla EA, Abu-Baker S et al.. Protein kinase C zeta represses the interleukin-6 promoter and impairs tumorigenesis in vivo. Mol Cell Biol. 2009; 29:104-115.
• [37]Scotti ML, Bamlet W, Smyrk TC, Fields AP, Murray NR. Protein kinase C iota is required for pancreatic cancer cell transformed growth and tumorigenesis. Cancer Res. 2010; 70:2064-2074.
• [38]Staiger K, Schatz U, Staiger H, Weyrich P, Haas C, Guirguis A et al.. Protein kinase C iota mediates lipid-induced apoptosis of human coronary artery endothelial cells. Microvasc Res. 2009; 78:40-44.
• [39]Kim JW, Chi V, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006; 66:8927-8930.
• [40]Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A et al.. Acidic extracellular microenvironment and cancer. Cancer Cell Int. 2013; 13:1-8. BioMed Central Full Text
• [41]Verma N, Vinayak M. Semecarpus anacardium nut extract promotes the antioxidant defence system and inhibits anaerobic metabolism during development of lymphoma. Biosci Rep. 2009; 29:151-164.
• [42]Mishra S and Vinayak M. Ellagic acid induces novel and atypical PKC isoforms and promotes caspase-3 dependent apoptosis by blocking energy metabolism. NutrCancer: An International Journal 2014, In Press DOI: 10.1080/01635581.2013.878735.