Screening of Fascaplysin for its Efficient Abatement of Hepatocellular Carcinoma and Promiscuous Epitope Mapping of Selected Proteins with Docking Perspectives
Keywords:
Aflatoxin, Hepatocellular carcinoma, Fascaplysin, Immunoinformatics, Epitope mappingAbstract
Hepatocellular carcinoma (HCC) is regarded as one among the deadliest cancers in the world. In particular, aflatoxin induced hepatocellular carcinoma is alarmingly on rise due to food contamination. However, several drugs and synthetic compound are reported to inhibit HCC in humans. Fascaplysin is a marine sponge derived compound has been increasingly considered and proved as a potential inhibitor of CDK2/CDK4 dependent kinase. In the present study, five proteins that are involved in activation of aflatoxin B1 induced hepatocellular carcinogenesis were selected and analyzed for its immunological profiling. Crystal structure of Human Glutathione S-Transferase (GST) A1, Prostaglandin H2 Synthase (PHS), Human Cytochrome p450 3A4, Human Microsomal P450 1A2 and p53 were assessed for their immunogenicity patterns. On the other hand, HLA B27 allele which plays a crucial role in cancer was chosen for T cell and B cell epitope mapping. In this analysis, it shows that SYFPEITHI immunogenic peptides were conserved in all the proteins envisaging the need for a common anti-cancer ligand. However, immunogenic assessment of epitopes and interacting residues revealed that fascaplysin interacts at multiple positions in binding amino acid residues of the selected proteins. This study is purely based on the immunoinformatics approach for the screening of specific compound which could suppress the hepatocellular carcinoma. Therefore, based on the results itÊs clear that fascaplysin is a potential inhibitor and effectively binds to immunogenic peptides and act as a candidate against aflatoxin induced hepatocellular carcinoma based on the Insilco analysis.
References
. Jemal A, Siegel R, Xu J, Ward E.
Cancer statistics. CA Cancer J
Clin. 2010; 5: 277ă300.
. Kobayashi T, Abe K, Asai K, Gomi K,
Juvvadi PR. Genomics of Aspergillus
oryzae. Biosci Biotechnol. Biochem
; 71: 646ă670.
. Nierman WC, Pain A, Anderson MJ,
Wortman JR, Kim HS. Genomic
sequence of the pathogenic and
allergenic filamentous fungus
Aspergillus fumigatus. Nature 2005; 438:
ă1156.
. Reddy KRN, Reddy CS, Muralidharan K.
Characterization of aflatoxin B1produced
by Aspergillus flavus isolated from
discolored rice grains. J Mycol Plant
Pathol 2005; 35: 470ă474.
. Speijers GJA, Speijers MHM. Combined
toxic effects of mycotoxins. Toxicol Lett
; 153: 91ă98.
. Allen TM, Cullis PR. Drug delivery
systems: entering the
mainstream. Science. 2004; 303: 1818ă
. Allen TM, Mumbengegwi DR, Charrois
GJ. Anti-CD19-targeted liposomal
doxorubicin improves the therapeutic
efficacy in murine B-cell lymphoma and
ameliorates the toxicity of liposomes
with varying drug release rates. Clin
Cancer Res. 2005; 11: 3567ă3573.
. Mac Diarmid JA, Mugridge NB, Weiss
JC, Phillips L, Burn AL. et al., Bacterially
derived 400 nm particles for
encapsulation and cancer cell targeting
of chemotherapeutics. Cancer Cell.
;11: 431-445.
. Lee TY, Wu HC, Tseng YL, Lin CT. A
novel peptide specifically binding to
nasopharyngeal carcinoma for targeted
drug delivery. Cancer Res. 2004; 64:
ă8008.
. Xiong XB, Huang Y, Lu WL, et al.,
Enhanced intracellular delivery and
improved antitumor efficacy of
doxorubicin by sterically stabilized
liposomes modified with a synthetic
RGD mimetic. J Control Release. 2005;
: 262ă275.
. Aoyama T, Yamano S, Guzelian PS,
Gelboin HV. Five of 12 forms of vaccinia
virus-expressed human hepatic
cytochrome P450 metabolically activates
aflatoxin B1. Proc. Natl Acad Sci. 1990;
: 4790ă4793.
. Crespi CL, Penman BW, Steimel DT,
Gelboin HV, Gonzalez FJ. The
development of human cell line stably
expressing human CYP3A4; role in the
metabolic activation of aflatoxin B1 and
comparison to CYP1A2 and CYP2A3.
Carcinogenesis. 1991; 12: 355ă359.
. Shimada T, Guengerich FP. Evidence
for cytochrome P-450NF, the nifedipine
oxidase, being the principal enzyme
involved in the bioactivation of aflatoxins
in human liver. Proc. Natl Acad Sci.
; 86: 462ă465.
. Yee C. Adoptive T cell therapy:
addressing challenges in cancer
immunotherapy. J Transl Med. 2005; 3:
. Knutson KL, Wagner W, Disis ML.
Adoptive T cell therapy of solid cancers.
Cancer Immunol Immunother. 2006; 55:
ă103.
. Ribas A, Timmerman JM, Butterfield LH,
Economou JS. Determinant spreading
and tumor responses after peptidebased cancer immunotherapy. Trends
Immunol. 2003; 24: 58-61.
. Maus MV, Thomas AK, Leonard DG, et
al., Ex vivo expansion of polyclonal and
antigen-specific cytotoxic T lymphocytes
by artificial APCs expressing ligands for
the T-cell receptor, CD28 and 4-1BB.
Nat Biotechnol. 2002; 20: 143ă148.
. De Luca DS. Blasczyk R. The immune -
informatics of cancer immunotherapy.
Tissue Antigens. 2007; 70: 265ă271.
. Brusic V, Petrovsky N.
Immunoinformatics ă the new kid in
town. Novartis Found Symp. 2003; 254:
ă13.
. Ahlers JD, Belyakov IM, Thomas EK,
Berzofsky JA. High affinity T helper
epitope induces complementary helper
and APC polarization, increased CTL,
and protection against viral infection. J
Clin Invest. 2001; 108: 1677ă1685.
. De Groot AS, Sbai H, Saint-Aubin C, Mc
Murry JA, Martin W. Immunoinformatics: mining genomes for vaccine
components. Immunol Cell Biol. 2002;
: 255ă269.
. Inaba H, Martin W, De Groot AS, Qin S,
De Groot LJ. Thyrotropin receptor
epitopes and their relation to
histocompatibility leukocyte antigen-DR
molecules in Graves' disease. J Clin
Endocrinol Metab. 2006; 91: 2286ă2294.
. Shafiq MI, Steinberger T, Schimd R.
Fascaplysin as a specific inhibitor for
CDK4: Insights from molecular
modeling. PLoS One. 2012; 7: e42612.
. Kensler TW, Qian GS, Chen JG,
Groopman JD. Ranslational strategies
for Cancer prevention in liver. Nature
Publishing Group. 2003; 3: 321 -329.
. Lukas B, Simone V, Heike J, Rowena B
Jurgen R. Nicotinamide
phosphoribosyltransferase and
prostaglandin H2 synthase 2 are upregulated in human pancreatic
adenocarcinoma cells after stimulation
with interleukin-1. Inter J of Onco. 2009;
: 97-107.
. Vogelstein B, Sur S, Prives C. p53: The
Most Frequently Altered Gene in Human
Cancers. Nature Education. 2010; 3: 6.
. Hayes JD, Flanagan JU, Jowsey IR.
Glutathione transferases. Annual
Review of Pharmacol Toxicol. 2005; 45:
. Eyerman MC, Wysocki L. T cell
recognition of somatically generated Ab
diversity. J Immunol.1994; 152: 1569ă
. Reveille JD. The genetic basis of
autoantibody production. Autoimmune
Rev.2006; 5: 389ă98.
. De Groot AS, Martin W. Reducing risk,
improving outcomes: bioengineering
less immunogenic protein therapeutics.
Clin Immunol. 2009; 131:189-201.
. Baloria U, Akhoon BA, Gupta SK,
Sharma S, Verma V. In silico proteomic
characterization of human epidermal
growth factor receptor 2 (HER-2) for the
mapping of high affinity antigenic
determinants against breast cancer.
Amino Acids. 2012; 42: 1349ă1360.
. Pedretti A, Villa L, Vistoli G. VEGA ă An
open platform to develop chemo-BioInformatics applications, using plug-in
architecture and script programming. J
Comput Aided Mol. 2004; 18: 167-73.
. Scofield RH, Warren WL, Koelsch G,
Harleyt JB. A hypothesis for the hla-b27
immune dys regulation in
Spondyloarthropathy: contributions from
enteric organisms, b27 Structure,
peptides bound by b27, and convergent
evolution. Proc Natl Acad Sci. 1993; 90:
-9334.
. Gupta SK, Srivastava M, Akhoon BA,
Smita S, Schmitz U, et al., Identification
of immunogenic consensus T-cell
epitopes in globally distributed influenzaA H1N1 neuraminidase. Infect Genet
Evol. 2010; 11: 308-319.
. Sette A, Fikes J. Epitope-based
vaccines: an update on epitope
identification, vaccine design and
delivery. Curr Opin Immunol. 2003; 15:
ă70.
. Calderone CT, Williams DH. An
enthalpic component in cooperativity:
the relationship between enthalpy,
entropy, and non-covalent structure in
weak associations. J Am Chem Soc.
; 123: 6262.
. Flower DR. Towards in silico prediction
of immunogenic epitopes. Trends
Immunol. 2003; 24: 667.
. Seifert UC, Maranon A, Shmueli JF,
Desoutter L, Wesoloski K, et al., An
essential role for tripeptidyl peptidase in
the generation of an MHC class I
epitope. Nat Immunol. 2003; 4: 375.
. Francois PY Lamour, Pilar Lardelli, Apfel
CM. Analysis of the ligand-binding
domain of human retinoic Acid Receptor
a by Site-Directed Mutagenesis. Mol Cell
Biol. 1996; 10: 5386ă5392.
. Llovet JM, Di Bisceglie AM, Bruix J et
al., Design and endpoints of clinical trials
in hepatocellular carcinoma. J Natl
Cancer Inst. 2008; 21: 698ă711.
. Cheng EH, Sheiko TV, Fisher JK,
Craigen WJ, Korsmeyer SJ. VDAC2
inhibits BAK activation and mitochondrial
apoptosis. Science. 2003; 301: 513ă
. Xiaojun Yan, Haimin Chen, Xiaoling Lu,
Feng Wang, Weifeng Xu, et al.,
Fascaplysin exert anti-tumor effects
through apoptotic and anti-angiogenesis
pathways in sarcoma mice model. Eur J
Pharmaceu Sci. 2011; 43: 251ă259.
