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      Apoptosis-induced effects of extract from Artemisia annua Linné by modulating PTEN/p53/PDK1/Akt/ signal pathways through PTEN/p53-independent manner in HCT116 colon cancer cells

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          Abstract

          Background

          The extracts from Artemisia annua Linné (AAE) has been known to possess various functions including anti-bacterial, anti-virus and anti-oxidant effects. However, the mechanism of those effects of AAE is not well known. Pursuantly, we determined the apoptotic effects of extract of AAE in HCT116 cell. In this study, we suggested that AAE may exert cancer cell apoptosis through PTEN/PDK1/Akt/p53signal pathway and mitochondria-mediated apoptotic proteins.

          Methods

          We measured 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) assay, Hoechst 33342 staining, Annexin V-PI staining, Mitopotential assay, immunofluorescence (IF) and Western blotting. Accordingly, our study showed that AAE treatment to HCT116 cells resulted in inhibition of PDK1, Akt, MDM2, Bcl-2, and pro-caspase 3 as well as activation of PTEN, p53-upregulated modulator of apoptosis (PUMA), Bax and Bak expression. Also we measured in vivo assay that xenograft model, H&E assay, TUNEL assay and IHC.

          Results

          AAE induced apoptosis via PTEN/p53/PDK1/Akt signal pathways through PTEN/p53-independent manner. AAE inhibit cell viability and increase LDH release in HCT116 colon cancer cell. Also, AAE increase apoptotic bodies, caspase −3,7 activation and reduces mitochondria membrane potential. AAE regulates cytochrome c translocation to the cytoplasm and Bax translocation to the mitochondrial membrane in an Immunofluorescence staining and increase PTEN and p53 expression in an in vivo tumor xenograft model. To elucidate the role of the PTEN/p53/PDK1/Akt signal pathways in cancer control, we conditionally inactivated PTEN/p53/PDK1/Akt signal pathways. We used inhibitors of PTEN, p53, PDK1, Akt. In consequence, these results indicate that AAE induced apoptosis by means of a mitochondrial event through the regulation of proteins such as Bax, Bak and cytochrome c in PDK1/Akt signaling pathways via PTEM/p53-independent manner.

          Conclusions

          We confirmed the apoptotic effect of extracts of AAE by Modulating PTEN/p53/PDK1/Akt/Signal Pathways through PTEN/p53-independent pathwaysin HCT116 colon cancer cell.

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          Most cited references24

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          Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.

          S Fulda, K-M Debatin (2006)
          Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homeostasis. One of the most important advances in cancer research in recent years is the recognition that cell death mostly by apoptosis is crucially involved in the regulation of tumor formation and also critically determines treatment response. Killing of tumor cells by most anticancer strategies currently used in clinical oncology, for example, chemotherapy, gamma-irradiation, suicide gene therapy or immunotherapy, has been linked to activation of apoptosis signal transduction pathways in cancer cells such as the intrinsic and/or extrinsic pathway. Thus, failure to undergo apoptosis may result in treatment resistance. Understanding the molecular events that regulate apoptosis in response to anticancer chemotherapy, and how cancer cells evade apoptotic death, provides novel opportunities for a more rational approach to develop molecular-targeted therapies for combating cancer.
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            Qinghaosu (artemisinin): an antimalarial drug from China.

            D L Klayman (1985)
            The herb Artemisia annua has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. In 1971, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This compound, called qinghaosu (QHS, artemisinin), is a sesquiterpene lactone that bears a peroxide grouping and, unlike most other antimalarials, lacks a nitrogen-containing heterocyclic ring system. The compound has been used successfully in several thousand malaria patients in China, including those with both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate, appear to be more potent than QHS itself. Sodium artesunate acts rapidly in restoring to consciousness comatose patients with cerebral malaria. Thus QHS and its derivatives offer promise as a totally new class of antimalarials.
            Article 0 comments Cited 251 times – based on 0 reviews     Review now
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              The mitochondrial p53 pathway.

              Angelina V Vaseva, Ute Moll (2009)
              p53 is one of the most mutated tumor suppressors in human cancers and as such has been intensively studied for a long time. p53 is a major orchestrator of the cellular response to a broad array of stress types by regulating apoptosis, cell cycle arrest, senescence, DNA repair and genetic stability. For a long time it was thought that these functions of p53 solely rely on its function as a transcription factor, and numerous p53 target genes have been identified [1]. In the last 8 years however, a novel transcription-independent proapoptotic function mediated by the cytoplasmic pool of p53 has been revealed. p53 participates directly in the intrinsic apoptosis pathway by interacting with the multidomain members of the Bcl-2 family to induce mitochondrial outer membrane permeabilization. Our review will discuss these studies, focusing on recent advances in the field.
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                Author and article information

                Contributors
                Eun Ji Kim: dms3003@naver.com
                Guen Tae Kim: kgt121@gmail.com
                Bo Min Kim: bomin308@naver.com
                Eun Gyeong Lim: dmsruddla99@naver.com
                Sang-Yong Kim: ksychj@naver.com
                Young Min Kim: +82-42-629-87 , kym@hnu.kr
                Journal
                Journal ID (nlm-ta): BMC Complement Altern Med
                Journal ID (iso-abbrev): BMC Complement Altern Med
                Title: BMC Complementary and Alternative Medicine
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1472-6882
                Publication date (Electronic): 28 April 2017
                Publication date PMC-release: 28 April 2017
                Publication date Collection: 2017
                Volume: 17
                Electronic Location Identifier: 236
                Affiliations
                [1 ]ISNI 0000 0004 0532 6499, GRID grid.411970.a, Department of Biological Science and Biotechnology, College of Life Science and Nano Technology, , Hannam University, ; 1646 Yuseong-daero, Yuseong-gu, Daejeon, 34054 Korea
                [2 ]Department of Food Science & Bio Technology, Shinansan University, Daehakro Danwon-gu, Ansan-city, Gyeonggi-do Korea
                Article
                Publisher ID: 1702
                DOI: 10.1186/s12906-017-1702-7
                PMC ID: 5410043
                PubMed ID: 28454566
                SO-VID: 2f3602eb-4ffe-4d8b-ba57-5acd2a1f5bf8
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 23 January 2017
                Date accepted : 23 March 2017
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Complementary & Alternative medicine
                Keywords: phosphatase and tensin homolog (pten),p53-independent manner,artemisia annua linné,apoptosis,hct116 colon cancer cell
                Data availability:
                ScienceOpen disciplines: Complementary & Alternative medicine
                Keywords: phosphatase and tensin homolog (pten), p53-independent manner, artemisia annua linné, apoptosis, hct116 colon cancer cell

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