Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress
Although some molecularly targeted drugs for colorectal cancer are used clinically and contribute to a better prognosis, the current median survival of advanced colorectal cancer patients is not sufficient. Autophagy, a basic cell survival mechanism mediated by recycling of cellular amino acids, pla...
Gespeichert in:
| Veröffentlicht in: | BMC cancer 2015-10, Vol.15 (1), p.795-795, Article 795 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 795 |
|---|---|
| container_issue | 1 |
| container_start_page | 795 |
| container_title | BMC cancer |
| container_volume | 15 |
| creator | Sakitani, Kosuke Hirata, Yoshihiro Hikiba, Yohko Hayakawa, Yoku Ihara, Sozaburo Suzuki, Hirobumi Suzuki, Nobumi Serizawa, Takako Kinoshita, Hiroto Sakamoto, Kei Nakagawa, Hayato Tateishi, Keisuke Maeda, Shin Ikenoue, Tsuneo Kawazu, Shoji Koike, Kazuhiko |
| description | Although some molecularly targeted drugs for colorectal cancer are used clinically and contribute to a better prognosis, the current median survival of advanced colorectal cancer patients is not sufficient. Autophagy, a basic cell survival mechanism mediated by recycling of cellular amino acids, plays an important role in cancer. Recently, autophagy has been highlighted as a promising new molecular target. The unfolded protein response (UPR) reportedly act in complementary fashion with autophagy in intestinal homeostasis. However, the roles of UPR in colon cancer under autophagic inhibition remain to be elucidated. We aim to clarify the inhibitory effect of autophagy on colon cancer.
We crossed K19 (CreERT) and Atg5 (flox/flox) mice to generate Atg5 (flox/flox)/K19 (CreERT) mice. Atg5 (flox/flox)/K19 (CreERT) mice were first treated with azoxymethane/dextran sodium sulfate and then injected with tamoxifen to inhibit autophagy in CK19-positive epithelial cells. To examine the anti-cancer mechanisms of autophagic inhibition, we used colon cancer cell lines harboring different p53 gene statuses, as well as small interfering RNAs (siRNAs) targeting Atg5 and immunoglobulin heavy-chain binding protein (BiP), a chaperone to aid folding of unfolded proteins.
Colon tumors in Atg5 (flox/flox)/K19 (CreERT) mice showed loss of autophagic activity and decreased tumor size (the total tumor diameter was 28.1 mm in the control and 20.7 mm in Atg5 (flox/flox)/K19 (CreERT) mice, p = 0.036). We found that p53 and UPR/endoplasmic reticulum (ER) stress-related proteins, such as cleaved caspase 3, and CAAT/enhancer-binding protein homologous protein, are up-regulated in colon tumors of Atg5 (flox/flox)/K19 (CreERT) mice. Although Atg5 and BiP silencing, respectively, increased apoptosis in p53 wild type cells, Atg5 silencing alone did not show the same effect on apoptosis in p53 mutant cells. However, co-transfection of Atg5 and BiP siRNAs led to increased apoptosis in p53 mutant cells.
Blocking autophagy has potential in the treatment of colon cancer by inducing apoptosis via p53 and ER stress, and suppressing the UPR pathway is a valid strategy to overcome resistance to autophagic inhibition. |
| doi_str_mv | 10.1186/s12885-015-1789-5 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4620020</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A541402308</galeid><sourcerecordid>A541402308</sourcerecordid><originalsourceid>FETCH-LOGICAL-c695t-9bdcaad4a0a613abc768fb19cf231a7cb594425a3970368f7aa6dfc39bf360783</originalsourceid><addsrcrecordid>eNptkl9rFDEUxQdRbK1-AF8kIIg-TM2fmcnkpVBK1YWCUPU53MkkuymzyZhklu63N-PWuiOSh4Sc3z1Jbk5RvCb4nJC2-RgJbdu6xKQuCW9FWT8pTknFSUkrzJ8erU-KFzHeYZwp3D4vTmhTiaZl7LRwK7exnU3WO-QNgin5cQPrPdL3OqSIwCVbKj9kWYFTOiBtjFZZ2VlAMPox-Wgjsq6flO5Rt0djzRCoZHfw2xVcj65vUUxBx_iyeGZgiPrVw3xW_Ph0_f3qS3nz9fPq6vKmVI2oUym6XgH0FWBoCINO8aY1HRHKUEaAq64WVUVrYIJjliUO0PRGMdEZ1mDesrPi4uA7Tt1W90q7FGCQY7BbCHvpwcql4uxGrv1OVg3FmOJs8P7BIPifk45Jbm1UehjAaT9FSTjlQmDakoy-_Qe981Nw-XmZ4qKlNRH8L7WGQUvrjM_nqtlUXtYVqTBleL73-X-oPHq9tco7bWzeXxR8WBRkJun7tIYpRrn6drtk3x2xGw1D2kQ_TPM3xSVIDqAKPsagzWPjCJZz8uQheTInT87Jk3WueXPc8ceKP1FjvwA5XtJ3</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1779825197</pqid></control><display><type>article</type><title>Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>SpringerLink Journals</source><source>PubMed Central Open Access</source><source>Springer Nature OA Free Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Sakitani, Kosuke ; Hirata, Yoshihiro ; Hikiba, Yohko ; Hayakawa, Yoku ; Ihara, Sozaburo ; Suzuki, Hirobumi ; Suzuki, Nobumi ; Serizawa, Takako ; Kinoshita, Hiroto ; Sakamoto, Kei ; Nakagawa, Hayato ; Tateishi, Keisuke ; Maeda, Shin ; Ikenoue, Tsuneo ; Kawazu, Shoji ; Koike, Kazuhiko</creator><creatorcontrib>Sakitani, Kosuke ; Hirata, Yoshihiro ; Hikiba, Yohko ; Hayakawa, Yoku ; Ihara, Sozaburo ; Suzuki, Hirobumi ; Suzuki, Nobumi ; Serizawa, Takako ; Kinoshita, Hiroto ; Sakamoto, Kei ; Nakagawa, Hayato ; Tateishi, Keisuke ; Maeda, Shin ; Ikenoue, Tsuneo ; Kawazu, Shoji ; Koike, Kazuhiko</creatorcontrib><description>Although some molecularly targeted drugs for colorectal cancer are used clinically and contribute to a better prognosis, the current median survival of advanced colorectal cancer patients is not sufficient. Autophagy, a basic cell survival mechanism mediated by recycling of cellular amino acids, plays an important role in cancer. Recently, autophagy has been highlighted as a promising new molecular target. The unfolded protein response (UPR) reportedly act in complementary fashion with autophagy in intestinal homeostasis. However, the roles of UPR in colon cancer under autophagic inhibition remain to be elucidated. We aim to clarify the inhibitory effect of autophagy on colon cancer.
We crossed K19 (CreERT) and Atg5 (flox/flox) mice to generate Atg5 (flox/flox)/K19 (CreERT) mice. Atg5 (flox/flox)/K19 (CreERT) mice were first treated with azoxymethane/dextran sodium sulfate and then injected with tamoxifen to inhibit autophagy in CK19-positive epithelial cells. To examine the anti-cancer mechanisms of autophagic inhibition, we used colon cancer cell lines harboring different p53 gene statuses, as well as small interfering RNAs (siRNAs) targeting Atg5 and immunoglobulin heavy-chain binding protein (BiP), a chaperone to aid folding of unfolded proteins.
Colon tumors in Atg5 (flox/flox)/K19 (CreERT) mice showed loss of autophagic activity and decreased tumor size (the total tumor diameter was 28.1 mm in the control and 20.7 mm in Atg5 (flox/flox)/K19 (CreERT) mice, p = 0.036). We found that p53 and UPR/endoplasmic reticulum (ER) stress-related proteins, such as cleaved caspase 3, and CAAT/enhancer-binding protein homologous protein, are up-regulated in colon tumors of Atg5 (flox/flox)/K19 (CreERT) mice. Although Atg5 and BiP silencing, respectively, increased apoptosis in p53 wild type cells, Atg5 silencing alone did not show the same effect on apoptosis in p53 mutant cells. However, co-transfection of Atg5 and BiP siRNAs led to increased apoptosis in p53 mutant cells.
Blocking autophagy has potential in the treatment of colon cancer by inducing apoptosis via p53 and ER stress, and suppressing the UPR pathway is a valid strategy to overcome resistance to autophagic inhibition.</description><identifier>ISSN: 1471-2407</identifier><identifier>EISSN: 1471-2407</identifier><identifier>DOI: 10.1186/s12885-015-1789-5</identifier><identifier>PMID: 26496833</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Amino acids ; Animals ; Antibodies ; Antigens ; Apoptosis ; Apoptosis - physiology ; Autophagy ; Autophagy - physiology ; Cancer ; Cell Line, Tumor ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - prevention & control ; Colorectal cancer ; Drug therapy ; Endoplasmic Reticulum Stress - physiology ; Gastrointestinal diseases ; Genes, p53 - physiology ; Growth factors ; HCT116 Cells ; Health aspects ; Homeostasis ; Humans ; Kinases ; Laboratories ; Medical prognosis ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Prevention ; Prognosis ; Proteins ; Tumor proteins ; Tumor Suppressor Protein p53 - biosynthesis ; Tumors</subject><ispartof>BMC cancer, 2015-10, Vol.15 (1), p.795-795, Article 795</ispartof><rights>COPYRIGHT 2015 BioMed Central Ltd.</rights><rights>Copyright BioMed Central 2015</rights><rights>Sakitani et al. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c695t-9bdcaad4a0a613abc768fb19cf231a7cb594425a3970368f7aa6dfc39bf360783</citedby><cites>FETCH-LOGICAL-c695t-9bdcaad4a0a613abc768fb19cf231a7cb594425a3970368f7aa6dfc39bf360783</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620020/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620020/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26496833$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sakitani, Kosuke</creatorcontrib><creatorcontrib>Hirata, Yoshihiro</creatorcontrib><creatorcontrib>Hikiba, Yohko</creatorcontrib><creatorcontrib>Hayakawa, Yoku</creatorcontrib><creatorcontrib>Ihara, Sozaburo</creatorcontrib><creatorcontrib>Suzuki, Hirobumi</creatorcontrib><creatorcontrib>Suzuki, Nobumi</creatorcontrib><creatorcontrib>Serizawa, Takako</creatorcontrib><creatorcontrib>Kinoshita, Hiroto</creatorcontrib><creatorcontrib>Sakamoto, Kei</creatorcontrib><creatorcontrib>Nakagawa, Hayato</creatorcontrib><creatorcontrib>Tateishi, Keisuke</creatorcontrib><creatorcontrib>Maeda, Shin</creatorcontrib><creatorcontrib>Ikenoue, Tsuneo</creatorcontrib><creatorcontrib>Kawazu, Shoji</creatorcontrib><creatorcontrib>Koike, Kazuhiko</creatorcontrib><title>Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress</title><title>BMC cancer</title><addtitle>BMC Cancer</addtitle><description>Although some molecularly targeted drugs for colorectal cancer are used clinically and contribute to a better prognosis, the current median survival of advanced colorectal cancer patients is not sufficient. Autophagy, a basic cell survival mechanism mediated by recycling of cellular amino acids, plays an important role in cancer. Recently, autophagy has been highlighted as a promising new molecular target. The unfolded protein response (UPR) reportedly act in complementary fashion with autophagy in intestinal homeostasis. However, the roles of UPR in colon cancer under autophagic inhibition remain to be elucidated. We aim to clarify the inhibitory effect of autophagy on colon cancer.
We crossed K19 (CreERT) and Atg5 (flox/flox) mice to generate Atg5 (flox/flox)/K19 (CreERT) mice. Atg5 (flox/flox)/K19 (CreERT) mice were first treated with azoxymethane/dextran sodium sulfate and then injected with tamoxifen to inhibit autophagy in CK19-positive epithelial cells. To examine the anti-cancer mechanisms of autophagic inhibition, we used colon cancer cell lines harboring different p53 gene statuses, as well as small interfering RNAs (siRNAs) targeting Atg5 and immunoglobulin heavy-chain binding protein (BiP), a chaperone to aid folding of unfolded proteins.
Colon tumors in Atg5 (flox/flox)/K19 (CreERT) mice showed loss of autophagic activity and decreased tumor size (the total tumor diameter was 28.1 mm in the control and 20.7 mm in Atg5 (flox/flox)/K19 (CreERT) mice, p = 0.036). We found that p53 and UPR/endoplasmic reticulum (ER) stress-related proteins, such as cleaved caspase 3, and CAAT/enhancer-binding protein homologous protein, are up-regulated in colon tumors of Atg5 (flox/flox)/K19 (CreERT) mice. Although Atg5 and BiP silencing, respectively, increased apoptosis in p53 wild type cells, Atg5 silencing alone did not show the same effect on apoptosis in p53 mutant cells. However, co-transfection of Atg5 and BiP siRNAs led to increased apoptosis in p53 mutant cells.
Blocking autophagy has potential in the treatment of colon cancer by inducing apoptosis via p53 and ER stress, and suppressing the UPR pathway is a valid strategy to overcome resistance to autophagic inhibition.</description><subject>Amino acids</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antigens</subject><subject>Apoptosis</subject><subject>Apoptosis - physiology</subject><subject>Autophagy</subject><subject>Autophagy - physiology</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - prevention & control</subject><subject>Colorectal cancer</subject><subject>Drug therapy</subject><subject>Endoplasmic Reticulum Stress - physiology</subject><subject>Gastrointestinal diseases</subject><subject>Genes, p53 - physiology</subject><subject>Growth factors</subject><subject>HCT116 Cells</subject><subject>Health aspects</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Medical prognosis</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Prevention</subject><subject>Prognosis</subject><subject>Proteins</subject><subject>Tumor proteins</subject><subject>Tumor Suppressor Protein p53 - biosynthesis</subject><subject>Tumors</subject><issn>1471-2407</issn><issn>1471-2407</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNptkl9rFDEUxQdRbK1-AF8kIIg-TM2fmcnkpVBK1YWCUPU53MkkuymzyZhklu63N-PWuiOSh4Sc3z1Jbk5RvCb4nJC2-RgJbdu6xKQuCW9FWT8pTknFSUkrzJ8erU-KFzHeYZwp3D4vTmhTiaZl7LRwK7exnU3WO-QNgin5cQPrPdL3OqSIwCVbKj9kWYFTOiBtjFZZ2VlAMPox-Wgjsq6flO5Rt0djzRCoZHfw2xVcj65vUUxBx_iyeGZgiPrVw3xW_Ph0_f3qS3nz9fPq6vKmVI2oUym6XgH0FWBoCINO8aY1HRHKUEaAq64WVUVrYIJjliUO0PRGMdEZ1mDesrPi4uA7Tt1W90q7FGCQY7BbCHvpwcql4uxGrv1OVg3FmOJs8P7BIPifk45Jbm1UehjAaT9FSTjlQmDakoy-_Qe981Nw-XmZ4qKlNRH8L7WGQUvrjM_nqtlUXtYVqTBleL73-X-oPHq9tco7bWzeXxR8WBRkJun7tIYpRrn6drtk3x2xGw1D2kQ_TPM3xSVIDqAKPsagzWPjCJZz8uQheTInT87Jk3WueXPc8ceKP1FjvwA5XtJ3</recordid><startdate>20151024</startdate><enddate>20151024</enddate><creator>Sakitani, Kosuke</creator><creator>Hirata, Yoshihiro</creator><creator>Hikiba, Yohko</creator><creator>Hayakawa, Yoku</creator><creator>Ihara, Sozaburo</creator><creator>Suzuki, Hirobumi</creator><creator>Suzuki, Nobumi</creator><creator>Serizawa, Takako</creator><creator>Kinoshita, Hiroto</creator><creator>Sakamoto, Kei</creator><creator>Nakagawa, Hayato</creator><creator>Tateishi, Keisuke</creator><creator>Maeda, Shin</creator><creator>Ikenoue, Tsuneo</creator><creator>Kawazu, Shoji</creator><creator>Koike, Kazuhiko</creator><general>BioMed Central Ltd</general><general>BioMed Central</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>ISR</scope><scope>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20151024</creationdate><title>Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress</title><author>Sakitani, Kosuke ; Hirata, Yoshihiro ; Hikiba, Yohko ; Hayakawa, Yoku ; Ihara, Sozaburo ; Suzuki, Hirobumi ; Suzuki, Nobumi ; Serizawa, Takako ; Kinoshita, Hiroto ; Sakamoto, Kei ; Nakagawa, Hayato ; Tateishi, Keisuke ; Maeda, Shin ; Ikenoue, Tsuneo ; Kawazu, Shoji ; Koike, Kazuhiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c695t-9bdcaad4a0a613abc768fb19cf231a7cb594425a3970368f7aa6dfc39bf360783</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Amino acids</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antigens</topic><topic>Apoptosis</topic><topic>Apoptosis - physiology</topic><topic>Autophagy</topic><topic>Autophagy - physiology</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Colonic Neoplasms - metabolism</topic><topic>Colonic Neoplasms - prevention & control</topic><topic>Colorectal cancer</topic><topic>Drug therapy</topic><topic>Endoplasmic Reticulum Stress - physiology</topic><topic>Gastrointestinal diseases</topic><topic>Genes, p53 - physiology</topic><topic>Growth factors</topic><topic>HCT116 Cells</topic><topic>Health aspects</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Medical prognosis</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Prevention</topic><topic>Prognosis</topic><topic>Proteins</topic><topic>Tumor proteins</topic><topic>Tumor Suppressor Protein p53 - biosynthesis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sakitani, Kosuke</creatorcontrib><creatorcontrib>Hirata, Yoshihiro</creatorcontrib><creatorcontrib>Hikiba, Yohko</creatorcontrib><creatorcontrib>Hayakawa, Yoku</creatorcontrib><creatorcontrib>Ihara, Sozaburo</creatorcontrib><creatorcontrib>Suzuki, Hirobumi</creatorcontrib><creatorcontrib>Suzuki, Nobumi</creatorcontrib><creatorcontrib>Serizawa, Takako</creatorcontrib><creatorcontrib>Kinoshita, Hiroto</creatorcontrib><creatorcontrib>Sakamoto, Kei</creatorcontrib><creatorcontrib>Nakagawa, Hayato</creatorcontrib><creatorcontrib>Tateishi, Keisuke</creatorcontrib><creatorcontrib>Maeda, Shin</creatorcontrib><creatorcontrib>Ikenoue, Tsuneo</creatorcontrib><creatorcontrib>Kawazu, Shoji</creatorcontrib><creatorcontrib>Koike, Kazuhiko</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>BMC cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sakitani, Kosuke</au><au>Hirata, Yoshihiro</au><au>Hikiba, Yohko</au><au>Hayakawa, Yoku</au><au>Ihara, Sozaburo</au><au>Suzuki, Hirobumi</au><au>Suzuki, Nobumi</au><au>Serizawa, Takako</au><au>Kinoshita, Hiroto</au><au>Sakamoto, Kei</au><au>Nakagawa, Hayato</au><au>Tateishi, Keisuke</au><au>Maeda, Shin</au><au>Ikenoue, Tsuneo</au><au>Kawazu, Shoji</au><au>Koike, Kazuhiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress</atitle><jtitle>BMC cancer</jtitle><addtitle>BMC Cancer</addtitle><date>2015-10-24</date><risdate>2015</risdate><volume>15</volume><issue>1</issue><spage>795</spage><epage>795</epage><pages>795-795</pages><artnum>795</artnum><issn>1471-2407</issn><eissn>1471-2407</eissn><abstract>Although some molecularly targeted drugs for colorectal cancer are used clinically and contribute to a better prognosis, the current median survival of advanced colorectal cancer patients is not sufficient. Autophagy, a basic cell survival mechanism mediated by recycling of cellular amino acids, plays an important role in cancer. Recently, autophagy has been highlighted as a promising new molecular target. The unfolded protein response (UPR) reportedly act in complementary fashion with autophagy in intestinal homeostasis. However, the roles of UPR in colon cancer under autophagic inhibition remain to be elucidated. We aim to clarify the inhibitory effect of autophagy on colon cancer.
We crossed K19 (CreERT) and Atg5 (flox/flox) mice to generate Atg5 (flox/flox)/K19 (CreERT) mice. Atg5 (flox/flox)/K19 (CreERT) mice were first treated with azoxymethane/dextran sodium sulfate and then injected with tamoxifen to inhibit autophagy in CK19-positive epithelial cells. To examine the anti-cancer mechanisms of autophagic inhibition, we used colon cancer cell lines harboring different p53 gene statuses, as well as small interfering RNAs (siRNAs) targeting Atg5 and immunoglobulin heavy-chain binding protein (BiP), a chaperone to aid folding of unfolded proteins.
Colon tumors in Atg5 (flox/flox)/K19 (CreERT) mice showed loss of autophagic activity and decreased tumor size (the total tumor diameter was 28.1 mm in the control and 20.7 mm in Atg5 (flox/flox)/K19 (CreERT) mice, p = 0.036). We found that p53 and UPR/endoplasmic reticulum (ER) stress-related proteins, such as cleaved caspase 3, and CAAT/enhancer-binding protein homologous protein, are up-regulated in colon tumors of Atg5 (flox/flox)/K19 (CreERT) mice. Although Atg5 and BiP silencing, respectively, increased apoptosis in p53 wild type cells, Atg5 silencing alone did not show the same effect on apoptosis in p53 mutant cells. However, co-transfection of Atg5 and BiP siRNAs led to increased apoptosis in p53 mutant cells.
Blocking autophagy has potential in the treatment of colon cancer by inducing apoptosis via p53 and ER stress, and suppressing the UPR pathway is a valid strategy to overcome resistance to autophagic inhibition.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>26496833</pmid><doi>10.1186/s12885-015-1789-5</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1471-2407 |
| ispartof | BMC cancer, 2015-10, Vol.15 (1), p.795-795, Article 795 |
| issn | 1471-2407 1471-2407 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4620020 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; SpringerLink Journals; PubMed Central Open Access; Springer Nature OA Free Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Amino acids Animals Antibodies Antigens Apoptosis Apoptosis - physiology Autophagy Autophagy - physiology Cancer Cell Line, Tumor Colonic Neoplasms - metabolism Colonic Neoplasms - prevention & control Colorectal cancer Drug therapy Endoplasmic Reticulum Stress - physiology Gastrointestinal diseases Genes, p53 - physiology Growth factors HCT116 Cells Health aspects Homeostasis Humans Kinases Laboratories Medical prognosis Mice Mice, Inbred C57BL Mice, Transgenic Prevention Prognosis Proteins Tumor proteins Tumor Suppressor Protein p53 - biosynthesis Tumors |
| title | Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T03%3A54%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Inhibition%20of%20autophagy%20exerts%20anti-colon%20cancer%20effects%20via%20apoptosis%20induced%20by%20p53%20activation%20and%20ER%20stress&rft.jtitle=BMC%20cancer&rft.au=Sakitani,%20Kosuke&rft.date=2015-10-24&rft.volume=15&rft.issue=1&rft.spage=795&rft.epage=795&rft.pages=795-795&rft.artnum=795&rft.issn=1471-2407&rft.eissn=1471-2407&rft_id=info:doi/10.1186/s12885-015-1789-5&rft_dat=%3Cgale_pubme%3EA541402308%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1779825197&rft_id=info:pmid/26496833&rft_galeid=A541402308&rfr_iscdi=true |