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      Molecular attributes and apoptosis-inducing activities of a putative serine protease isolated from Tiger Milk mushroom ( Lignosus rhinocerus) sclerotium against breast cancer cells in vitro

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          Abstract

          Background

          The highly valued medicinal tiger milk mushroom (also known as Lignosus rhinocerus) has the ability to cure numerous ailments. Its anticancer activities are well explored, and recently a partially purified cytotoxic protein fraction termed F5 from the mushroom’s sclerotial cold water extract consisting mainly of fungal serine proteases was found to exhibit potent selective cytotoxicity against a human breast adenocarcinoma cell line (MCF7) with IC 50 value of 3.00 μg/ml. However, characterization of its cell death-inducing activity has yet to be established.

          Methods

          The mechanism involved in the cytotoxic activities of F5 against MCF7 cells was elucidated by flow cytometry-based apoptosis detection, caspases activity measurement, and expression profiling of apoptosis markers by western blotting. Molecular attributes of F5 were further mined from L. rhinocerus’s published genome and transcriptome for future exploration.

          Results and Discussion

          Apoptosis induction in MCF7 cells by F5 may involve a cross-talk between the extrinsic and intrinsic apoptotic pathways with upregulation of caspase-8 and -9 activities and a marked decrease of Bcl-2. On the other hand, the levels of pro-apoptotic Bax, BID, and cleaved BID were increased accompanied by observable actin cleavage. At gene level, F5 composed of three predicted non-synonymous single nucleotide polymorphisms (T > C) and an alternative 5′ splice site.

          Conclusions

          Findings from this study provide an advanced framework for further investigations on cancer therapeutics development from L. rhinocerus.

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          Most cited references34

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          ProtTest: selection of best-fit models of protein evolution.

          Using an appropriate model of amino acid replacement is very important for the study of protein evolution and phylogenetic inference. We have built a tool for the selection of the best-fit model of evolution, among a set of candidate models, for a given protein sequence alignment. ProtTest is available under the GNU license from http://darwin.uvigo.es
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            Caspases: killer proteases

            Caspases (cysteinyl aspartate-specific proteinases) mediate highly specific proteolytic cleavage events in dying cells, which collectively manifest the apoptotic phenotype. The key and central role that these enzymes play in a biochemical cell-suicide pathway has been conserved throughout the evolution of multicellular eukaryotes.
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              Caspase-8 in apoptosis: the beginning of "the end"?

              Caspase-8 is a member of the cysteine proteases, which are implicated in apoptosis and cytokine processing. Like all caspases, caspase-8 is synthesized as an inactive single polypeptide chain zymogen procaspase and is activated by proteolytic cleavage, through either autoactivation after recruitment into a multimeric complex or trans-cleavage by other caspases. Thus, ligand binding-induced trimerization of death receptors results in recruitment of the receptor-specific adapter protein Fas-associated death domain (FADD), which then recruits caspase-8. Activated caspase-8 is known to propagate the apoptotic signal either by directly cleaving and activating downstream caspases or by cleaving the BH3 Bcl2-interacting protein, which leads to the release of cytochrome c from mitochondria, triggering activation of caspase-9 in a complex with dATP and Apaf-1. Activated caspase-9 then activates further "downstream caspases," including caspase-8. Knockout data indicate that caspase-8 is required for killing induced by the death receptors Fas, tumor necrosis factor receptor 1, and death receptor 3. Moreover, caspase-8-/- mice die in utero as a result of defective development of heart muscle and display fewer hematopoietic progenitor cells, suggesting that the FADD/caspase-8 pathway is absolutely required for growth and development of specific cell types.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                PeerJ
                PeerJ
                PeerJ
                PeerJ Inc. (San Francisco, USA )
                2167-8359
                5 June 2018
                2018
                : 6
                : e4940
                Affiliations
                [1 ] Department of Oral Biology, Faculty of Dentistry, MAHSA University , Kuala Lumpur, Malaysia
                [2 ] Medicinal Mushroom Research Group, Department of Molecular Medicine, Faculty of Medicine, University of Malaya , Kuala Lumpur, Wilayah Persekutuan, Malaysia
                [3 ] Ligno Biotech Sdn Bhd , Balakong Jaya, Selangor, Malaysia
                [4 ] Center for Natural Products Research and Drug Discovery, University of Malaya , Kuala Lumpur, Malaysia
                Article
                4940
                10.7717/peerj.4940
                5993024
                7f9d0046-cf3a-4c4e-8715-650bc6e032aa
                © 2018 Yap et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 9 March 2018
                : 18 May 2018
                Funding
                Funded by: Fundamental Research Grant Scheme (FRGS) from the Ministry of Education Malaysia
                Award ID: FP029-2014A
                Funded by: MAHSA Research Grant from MAHSA University
                Award ID: RP122-09/17
                Funded by: UMRG Programme Grant from University of Malaya
                Award ID: RP034 A, B, C—17AFR
                This research was supported by the Fundamental Research Grant Scheme (FRGS) FP029-2014A from the Ministry of Education Malaysia and MAHSA Research Grant (RP122-09/17) from MAHSA University. It was also supported by the UMRG Programme Grant (RP034 A, B, C–17AFR) from the University of Malaya, Kuala Lumpur, Malaysia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Biochemistry
                Genetics
                Oncology
                Translational Medicine
                Data Mining and Machine Learning

                f5,tiger milk mushroom,serine protease,lignosus rhinocerus,anticancer,apoptosis,gme4347_g

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