Loading…

Induction of cancer cell apoptosis by a-tocopheryl succinate: Molecular pathways and structural requirements

The vitamin E analog a-tocopheryl succinate (a-TOS) can induce apoptosis. We show that the proapoptotic activity of a-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented a-TOS-triggered apoptosis. More selective effectors...

Full description

Saved in:

Bibliographic Details
Published in:	The FASEB journal 2001-02, Vol.15 (2), p.403
Main Authors:	Neuzil, J., Weber, T., Schroder, A., Lu, M., Ostermann, G., Gellert, N., Mayne, G.C., Olejnicka, Beata, Negre-Salvayre, A., Sticha, M., Coffey, R.J., Weber, C.
Format:	Article
Language:	English
Subjects:	Colon cancer MEDICIN MEDICINE Programmed cell death Protein kinase C Vitamin E succinate
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

cited_by
cites
container_end_page
container_issue	2
container_start_page	403
container_title	The FASEB journal
container_volume	15
creator	Neuzil, J. Weber, T. Schroder, A. Lu, M. Ostermann, G. Gellert, N. Mayne, G.C. Olejnicka, Beata Negre-Salvayre, A. Sticha, M. Coffey, R.J. Weber, C.
description	The vitamin E analog a-tocopheryl succinate (a-TOS) can induce apoptosis. We show that the proapoptotic activity of a-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented a-TOS-triggered apoptosis. More selective effectors indicated that a-TOS reduced PKCa isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCa inhibition in a-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCa overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of a-TOS-induced proapoptotic signals. Structural analogs revealed that a-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, a-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.
doi_str_mv	10.1096/fj.00-0251com
format	article
fullrecord	<record><control><sourceid>swepub</sourceid><recordid>TN_cdi_swepub_primary_oai_DiVA_org_liu_47470</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>oai_DiVA_org_liu_47470</sourcerecordid><originalsourceid>FETCH-LOGICAL-h670-478675a5930824fdfb1cdc9c6193e080c0164f9abd551dfa1f4a0a4877fb39003</originalsourceid><addsrcrecordid>eNotzk9LwzAYgPEcFJzTo_d8ADPfLP8a8DKmzsHAy_Aa3qaJy-ia0rRIv72Cnp7bj4eQBw4rDlY_xfMKgMFacZ8vV2TBlQCmKw035LaUMwBw4HpBnvddM_kx5Y7mSD12PgzUh7al2Od-zCUVWs8U2Zh97k9hmFtaJu9Th2O4I9cR2xLu_7skx7fX4_adHT52--3mwE7aAJOm0kahsgKqtYxNrLlvvPWaWxGgAv87IqPFulGKNxF5lAgoK2NiLSyAWJLHP7Z8h36qXT-kCw6zy5jcS_rcuDx8uTZNThppQPwAFoRLxg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Induction of cancer cell apoptosis by a-tocopheryl succinate: Molecular pathways and structural requirements</title><source>Wiley-Blackwell Read & Publish Collection</source><creator>Neuzil, J. ; Weber, T. ; Schroder, A. ; Lu, M. ; Ostermann, G. ; Gellert, N. ; Mayne, G.C. ; Olejnicka, Beata ; Negre-Salvayre, A. ; Sticha, M. ; Coffey, R.J. ; Weber, C.</creator><creatorcontrib>Neuzil, J. ; Weber, T. ; Schroder, A. ; Lu, M. ; Ostermann, G. ; Gellert, N. ; Mayne, G.C. ; Olejnicka, Beata ; Negre-Salvayre, A. ; Sticha, M. ; Coffey, R.J. ; Weber, C.</creatorcontrib><description>The vitamin E analog a-tocopheryl succinate (a-TOS) can induce apoptosis. We show that the proapoptotic activity of a-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented a-TOS-triggered apoptosis. More selective effectors indicated that a-TOS reduced PKCa isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCa inhibition in a-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCa overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of a-TOS-induced proapoptotic signals. Structural analogs revealed that a-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, a-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.</description><identifier>ISSN: 1530-6860</identifier><identifier>ISSN: 0892-6638</identifier><identifier>DOI: 10.1096/fj.00-0251com</identifier><language>eng</language><subject>Colon cancer ; MEDICIN ; MEDICINE ; Programmed cell death ; Protein kinase C ; Vitamin E succinate</subject><ispartof>The FASEB journal, 2001-02, Vol.15 (2), p.403</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-47470$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Neuzil, J.</creatorcontrib><creatorcontrib>Weber, T.</creatorcontrib><creatorcontrib>Schroder, A.</creatorcontrib><creatorcontrib>Lu, M.</creatorcontrib><creatorcontrib>Ostermann, G.</creatorcontrib><creatorcontrib>Gellert, N.</creatorcontrib><creatorcontrib>Mayne, G.C.</creatorcontrib><creatorcontrib>Olejnicka, Beata</creatorcontrib><creatorcontrib>Negre-Salvayre, A.</creatorcontrib><creatorcontrib>Sticha, M.</creatorcontrib><creatorcontrib>Coffey, R.J.</creatorcontrib><creatorcontrib>Weber, C.</creatorcontrib><title>Induction of cancer cell apoptosis by a-tocopheryl succinate: Molecular pathways and structural requirements</title><title>The FASEB journal</title><description>The vitamin E analog a-tocopheryl succinate (a-TOS) can induce apoptosis. We show that the proapoptotic activity of a-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented a-TOS-triggered apoptosis. More selective effectors indicated that a-TOS reduced PKCa isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCa inhibition in a-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCa overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of a-TOS-induced proapoptotic signals. Structural analogs revealed that a-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, a-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.</description><subject>Colon cancer</subject><subject>MEDICIN</subject><subject>MEDICINE</subject><subject>Programmed cell death</subject><subject>Protein kinase C</subject><subject>Vitamin E succinate</subject><issn>1530-6860</issn><issn>0892-6638</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><recordid>eNotzk9LwzAYgPEcFJzTo_d8ADPfLP8a8DKmzsHAy_Aa3qaJy-ia0rRIv72Cnp7bj4eQBw4rDlY_xfMKgMFacZ8vV2TBlQCmKw035LaUMwBw4HpBnvddM_kx5Y7mSD12PgzUh7al2Od-zCUVWs8U2Zh97k9hmFtaJu9Th2O4I9cR2xLu_7skx7fX4_adHT52--3mwE7aAJOm0kahsgKqtYxNrLlvvPWaWxGgAv87IqPFulGKNxF5lAgoK2NiLSyAWJLHP7Z8h36qXT-kCw6zy5jcS_rcuDx8uTZNThppQPwAFoRLxg</recordid><startdate>20010201</startdate><enddate>20010201</enddate><creator>Neuzil, J.</creator><creator>Weber, T.</creator><creator>Schroder, A.</creator><creator>Lu, M.</creator><creator>Ostermann, G.</creator><creator>Gellert, N.</creator><creator>Mayne, G.C.</creator><creator>Olejnicka, Beata</creator><creator>Negre-Salvayre, A.</creator><creator>Sticha, M.</creator><creator>Coffey, R.J.</creator><creator>Weber, C.</creator><scope>ADTPV</scope><scope>AOWAS</scope><scope>DG8</scope></search><sort><creationdate>20010201</creationdate><title>Induction of cancer cell apoptosis by a-tocopheryl succinate</title><author>Neuzil, J. ; Weber, T. ; Schroder, A. ; Lu, M. ; Ostermann, G. ; Gellert, N. ; Mayne, G.C. ; Olejnicka, Beata ; Negre-Salvayre, A. ; Sticha, M. ; Coffey, R.J. ; Weber, C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h670-478675a5930824fdfb1cdc9c6193e080c0164f9abd551dfa1f4a0a4877fb39003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Colon cancer</topic><topic>MEDICIN</topic><topic>MEDICINE</topic><topic>Programmed cell death</topic><topic>Protein kinase C</topic><topic>Vitamin E succinate</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Neuzil, J.</creatorcontrib><creatorcontrib>Weber, T.</creatorcontrib><creatorcontrib>Schroder, A.</creatorcontrib><creatorcontrib>Lu, M.</creatorcontrib><creatorcontrib>Ostermann, G.</creatorcontrib><creatorcontrib>Gellert, N.</creatorcontrib><creatorcontrib>Mayne, G.C.</creatorcontrib><creatorcontrib>Olejnicka, Beata</creatorcontrib><creatorcontrib>Negre-Salvayre, A.</creatorcontrib><creatorcontrib>Sticha, M.</creatorcontrib><creatorcontrib>Coffey, R.J.</creatorcontrib><creatorcontrib>Weber, C.</creatorcontrib><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Linköpings universitet</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Neuzil, J.</au><au>Weber, T.</au><au>Schroder, A.</au><au>Lu, M.</au><au>Ostermann, G.</au><au>Gellert, N.</au><au>Mayne, G.C.</au><au>Olejnicka, Beata</au><au>Negre-Salvayre, A.</au><au>Sticha, M.</au><au>Coffey, R.J.</au><au>Weber, C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Induction of cancer cell apoptosis by a-tocopheryl succinate: Molecular pathways and structural requirements</atitle><jtitle>The FASEB journal</jtitle><date>2001-02-01</date><risdate>2001</risdate><volume>15</volume><issue>2</issue><spage>403</spage><pages>403-</pages><issn>1530-6860</issn><issn>0892-6638</issn><abstract>The vitamin E analog a-tocopheryl succinate (a-TOS) can induce apoptosis. We show that the proapoptotic activity of a-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented a-TOS-triggered apoptosis. More selective effectors indicated that a-TOS reduced PKCa isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCa inhibition in a-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCa overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of a-TOS-induced proapoptotic signals. Structural analogs revealed that a-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, a-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.</abstract><doi>10.1096/fj.00-0251com</doi></addata></record>
fulltext	fulltext
identifier	ISSN: 1530-6860
ispartof	The FASEB journal, 2001-02, Vol.15 (2), p.403
issn	1530-6860 0892-6638
language	eng
recordid	cdi_swepub_primary_oai_DiVA_org_liu_47470
source	Wiley-Blackwell Read & Publish Collection
subjects	Colon cancer MEDICIN MEDICINE Programmed cell death Protein kinase C Vitamin E succinate
title	Induction of cancer cell apoptosis by a-tocopheryl succinate: Molecular pathways and structural requirements
url	http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T03%3A09%3A50IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-swepub&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Induction%20of%20cancer%20cell%20apoptosis%20by%20a-tocopheryl%20succinate:%20Molecular%20pathways%20and%20structural%20requirements&rft.jtitle=The%20FASEB%20journal&rft.au=Neuzil,%20J.&rft.date=2001-02-01&rft.volume=15&rft.issue=2&rft.spage=403&rft.pages=403-&rft.issn=1530-6860&rft_id=info:doi/10.1096/fj.00-0251com&rft_dat=%3Cswepub%3Eoai_DiVA_org_liu_47470%3C/swepub%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-h670-478675a5930824fdfb1cdc9c6193e080c0164f9abd551dfa1f4a0a4877fb39003%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_id=info:pmid/&rfr_iscdi=true