Requirement of c-Jun N-Terminal Kinase for Apoptotic Cell Death Induced by Farnesyltransferase Inhibitor, Farnesylamine, in Human Pancreatic Cancer Cells
Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs and are now in clinical trial. We have previously shown that farnesylamine, synthetic isoprenoid-linked with “amine” which acts as a potent FTI, induces apoptosis in human pancreatic cancer cells through the ras signal...
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| Veröffentlicht in: | Biochemical and biophysical research communications 2001-10, Vol.288 (1), p.198-204 |
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| creator | Mizukami, Yusuke Ura, Hitoshi Obara, Takeshi Habiro, Atsuya Izawa, Tsutomu Osanai, Manabu Yanagawa, Nobuyuki Tanno, Satoshi Kohgo, Yutaka |
| description | Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs and are now in clinical trial. We have previously shown that farnesylamine, synthetic isoprenoid-linked with “amine” which acts as a potent FTI, induces apoptosis in human pancreatic cancer cells through the ras signaling cascade. Since the effect of FTI is usually ‘cytostatic’ rather than ‘cytotoxic’, we speculated another apoptotic machinery of farnesylamine in addition to the effect of FTI. Farnesylamine induced sustained activation of c-jun N-terminal kinase (JNK), which was not caused by other FTI, FTI-277. Blockage of JNK activity by dominant-negative mutant abrogated the DNA laddering and significantly reduced ‘cytotoxic’ effect of farnesylamine. Strikingly similar effect on JNK activation and apoptosis was induced by structurally related long-chain fatty amine (LFA), oleylamine, but not by farnesol, an isoprenoid analogue of farnesylamine without “amine.” Taken together, apoptosis induction through JNK activation by farnesylamine based on the LFA structure rather than an effect of FTI. |
| doi_str_mv | 10.1006/bbrc.2001.5744 |
| format | Article |
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We have previously shown that farnesylamine, synthetic isoprenoid-linked with “amine” which acts as a potent FTI, induces apoptosis in human pancreatic cancer cells through the ras signaling cascade. Since the effect of FTI is usually ‘cytostatic’ rather than ‘cytotoxic’, we speculated another apoptotic machinery of farnesylamine in addition to the effect of FTI. Farnesylamine induced sustained activation of c-jun N-terminal kinase (JNK), which was not caused by other FTI, FTI-277. Blockage of JNK activity by dominant-negative mutant abrogated the DNA laddering and significantly reduced ‘cytotoxic’ effect of farnesylamine. Strikingly similar effect on JNK activation and apoptosis was induced by structurally related long-chain fatty amine (LFA), oleylamine, but not by farnesol, an isoprenoid analogue of farnesylamine without “amine.” Taken together, apoptosis induction through JNK activation by farnesylamine based on the LFA structure rather than an effect of FTI.</description><identifier>ISSN: 0006-291X</identifier><identifier>EISSN: 1090-2104</identifier><identifier>DOI: 10.1006/bbrc.2001.5744</identifier><identifier>PMID: 11594773</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alkyl and Aryl Transferases - antagonists & inhibitors ; Amines - pharmacology ; Antineoplastic Agents - pharmacology ; Apoptosis ; c-jun N-terminal kinase ; Enzyme Inhibitors - pharmacology ; Farnesol - analogs & derivatives ; Farnesol - pharmacology ; farnesyltransferase inhibitor ; Farnesyltranstransferase ; Genes, ras ; Humans ; isoprenoid ; JNK Mitogen-Activated Protein Kinases ; long-chain fatty amine ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinase 8 ; Mitogen-Activated Protein Kinases - antagonists & inhibitors ; Mitogen-Activated Protein Kinases - genetics ; Mitogen-Activated Protein Kinases - physiology ; Mutation ; pancreatic cancer ; Pancreatic Neoplasms - enzymology ; Pancreatic Neoplasms - pathology ; Tumor Cells, Cultured</subject><ispartof>Biochemical and biophysical research communications, 2001-10, Vol.288 (1), p.198-204</ispartof><rights>2001 Academic Press</rights><rights>Copyright 2001 Academic Press.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c340t-70610f35296c4f489496eac7b5ea65e90cb7fadb300deece83feb0f5af9130373</citedby><cites>FETCH-LOGICAL-c340t-70610f35296c4f489496eac7b5ea65e90cb7fadb300deece83feb0f5af9130373</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1006/bbrc.2001.5744$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11594773$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mizukami, Yusuke</creatorcontrib><creatorcontrib>Ura, Hitoshi</creatorcontrib><creatorcontrib>Obara, Takeshi</creatorcontrib><creatorcontrib>Habiro, Atsuya</creatorcontrib><creatorcontrib>Izawa, Tsutomu</creatorcontrib><creatorcontrib>Osanai, Manabu</creatorcontrib><creatorcontrib>Yanagawa, Nobuyuki</creatorcontrib><creatorcontrib>Tanno, Satoshi</creatorcontrib><creatorcontrib>Kohgo, Yutaka</creatorcontrib><title>Requirement of c-Jun N-Terminal Kinase for Apoptotic Cell Death Induced by Farnesyltransferase Inhibitor, Farnesylamine, in Human Pancreatic Cancer Cells</title><title>Biochemical and biophysical research communications</title><addtitle>Biochem Biophys Res Commun</addtitle><description>Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs and are now in clinical trial. We have previously shown that farnesylamine, synthetic isoprenoid-linked with “amine” which acts as a potent FTI, induces apoptosis in human pancreatic cancer cells through the ras signaling cascade. Since the effect of FTI is usually ‘cytostatic’ rather than ‘cytotoxic’, we speculated another apoptotic machinery of farnesylamine in addition to the effect of FTI. Farnesylamine induced sustained activation of c-jun N-terminal kinase (JNK), which was not caused by other FTI, FTI-277. Blockage of JNK activity by dominant-negative mutant abrogated the DNA laddering and significantly reduced ‘cytotoxic’ effect of farnesylamine. Strikingly similar effect on JNK activation and apoptosis was induced by structurally related long-chain fatty amine (LFA), oleylamine, but not by farnesol, an isoprenoid analogue of farnesylamine without “amine.” Taken together, apoptosis induction through JNK activation by farnesylamine based on the LFA structure rather than an effect of FTI.</description><subject>Alkyl and Aryl Transferases - antagonists & inhibitors</subject><subject>Amines - pharmacology</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>c-jun N-terminal kinase</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Farnesol - analogs & derivatives</subject><subject>Farnesol - pharmacology</subject><subject>farnesyltransferase inhibitor</subject><subject>Farnesyltranstransferase</subject><subject>Genes, ras</subject><subject>Humans</subject><subject>isoprenoid</subject><subject>JNK Mitogen-Activated Protein Kinases</subject><subject>long-chain fatty amine</subject><subject>MAP Kinase Signaling System</subject><subject>Mitogen-Activated Protein Kinase 8</subject><subject>Mitogen-Activated Protein Kinases - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinases - genetics</subject><subject>Mitogen-Activated Protein Kinases - physiology</subject><subject>Mutation</subject><subject>pancreatic cancer</subject><subject>Pancreatic Neoplasms - enzymology</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Tumor Cells, Cultured</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kcFu1DAQhi0EotvClSPyiVOzjBMnWR-rhbYLFSBUJG6W7YxVo8Te2g7SPgpvi8Ou4MTFY2m--WTPT8grBmsG0L3VOpp1DcDWbc_5E7JiIKCqGfCnZAWFqGrBvp-R85R-FIrxTjwnZ4y1gvd9syK_vuLj7CJO6DMNlprqw-zpp-oe4-S8GunHciakNkR6tQ_7HLIzdIvjSN-hyg9054fZ4ED1gV6r6DEdxhyVTxbjMrfzD067HOLl37YqYrykztPbeVKeflHexOJavOWK8Y8-vSDPrBoTvjzVC_Lt-v399ra6-3yz217dVabhkKseOga2aWvRGW75RnDRoTK9blF1LQowurdq0A3AgGhw01jUYFtlBWug6ZsL8ubo3cfwOGPKcnLJlBcoj2FOsq9ZkTIo4PoImhhSimjlPrpJxYNkIJcw5BKGXMKQSxhl4PXJPOsJh3_4afsF2BwBLP_76TDKZByWFQwlEZPlENz_3L8BJvea_Q</recordid><startdate>20011019</startdate><enddate>20011019</enddate><creator>Mizukami, Yusuke</creator><creator>Ura, Hitoshi</creator><creator>Obara, Takeshi</creator><creator>Habiro, Atsuya</creator><creator>Izawa, Tsutomu</creator><creator>Osanai, Manabu</creator><creator>Yanagawa, Nobuyuki</creator><creator>Tanno, Satoshi</creator><creator>Kohgo, Yutaka</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20011019</creationdate><title>Requirement of c-Jun N-Terminal Kinase for Apoptotic Cell Death Induced by Farnesyltransferase Inhibitor, Farnesylamine, in Human Pancreatic Cancer Cells</title><author>Mizukami, Yusuke ; Ura, Hitoshi ; Obara, Takeshi ; Habiro, Atsuya ; Izawa, Tsutomu ; Osanai, Manabu ; Yanagawa, Nobuyuki ; Tanno, Satoshi ; Kohgo, Yutaka</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c340t-70610f35296c4f489496eac7b5ea65e90cb7fadb300deece83feb0f5af9130373</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Alkyl and Aryl Transferases - antagonists & inhibitors</topic><topic>Amines - pharmacology</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>c-jun N-terminal kinase</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Farnesol - analogs & derivatives</topic><topic>Farnesol - pharmacology</topic><topic>farnesyltransferase inhibitor</topic><topic>Farnesyltranstransferase</topic><topic>Genes, ras</topic><topic>Humans</topic><topic>isoprenoid</topic><topic>JNK Mitogen-Activated Protein Kinases</topic><topic>long-chain fatty amine</topic><topic>MAP Kinase Signaling System</topic><topic>Mitogen-Activated Protein Kinase 8</topic><topic>Mitogen-Activated Protein Kinases - antagonists & inhibitors</topic><topic>Mitogen-Activated Protein Kinases - genetics</topic><topic>Mitogen-Activated Protein Kinases - physiology</topic><topic>Mutation</topic><topic>pancreatic cancer</topic><topic>Pancreatic Neoplasms - enzymology</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mizukami, Yusuke</creatorcontrib><creatorcontrib>Ura, Hitoshi</creatorcontrib><creatorcontrib>Obara, Takeshi</creatorcontrib><creatorcontrib>Habiro, Atsuya</creatorcontrib><creatorcontrib>Izawa, Tsutomu</creatorcontrib><creatorcontrib>Osanai, Manabu</creatorcontrib><creatorcontrib>Yanagawa, Nobuyuki</creatorcontrib><creatorcontrib>Tanno, Satoshi</creatorcontrib><creatorcontrib>Kohgo, Yutaka</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mizukami, Yusuke</au><au>Ura, Hitoshi</au><au>Obara, Takeshi</au><au>Habiro, Atsuya</au><au>Izawa, Tsutomu</au><au>Osanai, Manabu</au><au>Yanagawa, Nobuyuki</au><au>Tanno, Satoshi</au><au>Kohgo, Yutaka</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Requirement of c-Jun N-Terminal Kinase for Apoptotic Cell Death Induced by Farnesyltransferase Inhibitor, Farnesylamine, in Human Pancreatic Cancer Cells</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>2001-10-19</date><risdate>2001</risdate><volume>288</volume><issue>1</issue><spage>198</spage><epage>204</epage><pages>198-204</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><abstract>Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs and are now in clinical trial. We have previously shown that farnesylamine, synthetic isoprenoid-linked with “amine” which acts as a potent FTI, induces apoptosis in human pancreatic cancer cells through the ras signaling cascade. Since the effect of FTI is usually ‘cytostatic’ rather than ‘cytotoxic’, we speculated another apoptotic machinery of farnesylamine in addition to the effect of FTI. Farnesylamine induced sustained activation of c-jun N-terminal kinase (JNK), which was not caused by other FTI, FTI-277. Blockage of JNK activity by dominant-negative mutant abrogated the DNA laddering and significantly reduced ‘cytotoxic’ effect of farnesylamine. Strikingly similar effect on JNK activation and apoptosis was induced by structurally related long-chain fatty amine (LFA), oleylamine, but not by farnesol, an isoprenoid analogue of farnesylamine without “amine.” Taken together, apoptosis induction through JNK activation by farnesylamine based on the LFA structure rather than an effect of FTI.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>11594773</pmid><doi>10.1006/bbrc.2001.5744</doi><tpages>7</tpages></addata></record> |
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| ispartof | Biochemical and biophysical research communications, 2001-10, Vol.288 (1), p.198-204 |
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| subjects | Alkyl and Aryl Transferases - antagonists & inhibitors Amines - pharmacology Antineoplastic Agents - pharmacology Apoptosis c-jun N-terminal kinase Enzyme Inhibitors - pharmacology Farnesol - analogs & derivatives Farnesol - pharmacology farnesyltransferase inhibitor Farnesyltranstransferase Genes, ras Humans isoprenoid JNK Mitogen-Activated Protein Kinases long-chain fatty amine MAP Kinase Signaling System Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinases - genetics Mitogen-Activated Protein Kinases - physiology Mutation pancreatic cancer Pancreatic Neoplasms - enzymology Pancreatic Neoplasms - pathology Tumor Cells, Cultured |
| title | Requirement of c-Jun N-Terminal Kinase for Apoptotic Cell Death Induced by Farnesyltransferase Inhibitor, Farnesylamine, in Human Pancreatic Cancer Cells |
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