Ral GTPase promotes metastasis of pancreatic ductal adenocarcinoma via elevation of TGF-β1 production
Pancreatic ductal adenocarcinoma (PDAC), caused by activating mutations in K-Ras, is an aggressive malignancy due to its early invasion and metastasis. Ral GTPases are activated downstream of Ras and play a crucial role in the development and progression of PDAC. However, the underlying mechanisms r...
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| Veröffentlicht in: | The Journal of biological chemistry 2023-06, Vol.299 (6), p.104754-104754, Article 104754 |
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| creator | Cao, Mingxin Li, Xinming Trinh, Duc-Anh Yoshimachi, Shingo Goto, Kota Sakata, Natsumi Ishida, Masaharu Ohtsuka, Hideo Unno, Michiaki Wang, Yuxia Shirakawa, Ryutaro Horiuchi, Hisanori |
| description | Pancreatic ductal adenocarcinoma (PDAC), caused by activating mutations in K-Ras, is an aggressive malignancy due to its early invasion and metastasis. Ral GTPases are activated downstream of Ras and play a crucial role in the development and progression of PDAC. However, the underlying mechanisms remain unclear. In this study, we investigated the mechanism of Ral-induced invasion and metastasis of PDAC cells using RalGAPβ-deficient PDAC cells with highly activated Ral GTPases. Array analysis and ELISA revealed increased expression and secretion of TGF-β1 in RalGAPβ-deficient PDAC cells compared to control cells. Blockade of TGF-β1 signaling suppressed RalGAPβ deficiency-enhanced migration and invasion in vitro and metastasis in vivo to levels similar to controls. Phosphorylation of c-Jun N-terminal kinase, a repressor of TGF-β1 expression, was decreased by RalGAPβ deficiency. These results indicate that Ral contributes to invasion and metastasis of PDAC cells by elevating autocrine TGF-β1 signaling at least in part by decreasing c-Jun N-terminal kinase activity. |
| doi_str_mv | 10.1016/j.jbc.2023.104754 |
| format | Article |
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Ral GTPases are activated downstream of Ras and play a crucial role in the development and progression of PDAC. However, the underlying mechanisms remain unclear. In this study, we investigated the mechanism of Ral-induced invasion and metastasis of PDAC cells using RalGAPβ-deficient PDAC cells with highly activated Ral GTPases. Array analysis and ELISA revealed increased expression and secretion of TGF-β1 in RalGAPβ-deficient PDAC cells compared to control cells. Blockade of TGF-β1 signaling suppressed RalGAPβ deficiency-enhanced migration and invasion in vitro and metastasis in vivo to levels similar to controls. Phosphorylation of c-Jun N-terminal kinase, a repressor of TGF-β1 expression, was decreased by RalGAPβ deficiency. These results indicate that Ral contributes to invasion and metastasis of PDAC cells by elevating autocrine TGF-β1 signaling at least in part by decreasing c-Jun N-terminal kinase activity.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1016/j.jbc.2023.104754</identifier><identifier>PMID: 37116704</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Carcinoma, Pancreatic Ductal - metabolism ; Cell Line, Tumor ; Cell Movement ; Gene Expression Regulation, Neoplastic ; GTP Phosphohydrolases - metabolism ; Humans ; metastasis ; Mice ; Neoplasm Metastasis ; pancreatic ductal adenocarcinoma ; Pancreatic Neoplasms ; Pancreatic Neoplasms - pathology ; Ral GTPase ; RalGAP ; TGF-β1 ; Transforming Growth Factor beta1 - metabolism</subject><ispartof>The Journal of biological chemistry, 2023-06, Vol.299 (6), p.104754-104754, Article 104754</ispartof><rights>2023 The Authors</rights><rights>Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>2023 The Authors 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3674-400ffdffb5e6c87af556a29dc5e821c10e0faf7cfaccee95f403b05ad548c0d33</citedby><cites>FETCH-LOGICAL-c3674-400ffdffb5e6c87af556a29dc5e821c10e0faf7cfaccee95f403b05ad548c0d33</cites><orcidid>0000-0002-2145-6416 ; 0000-0003-4315-7131 ; 0000-0002-8823-6696</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10220265/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10220265/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37116704$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cao, Mingxin</creatorcontrib><creatorcontrib>Li, Xinming</creatorcontrib><creatorcontrib>Trinh, Duc-Anh</creatorcontrib><creatorcontrib>Yoshimachi, Shingo</creatorcontrib><creatorcontrib>Goto, Kota</creatorcontrib><creatorcontrib>Sakata, Natsumi</creatorcontrib><creatorcontrib>Ishida, Masaharu</creatorcontrib><creatorcontrib>Ohtsuka, Hideo</creatorcontrib><creatorcontrib>Unno, Michiaki</creatorcontrib><creatorcontrib>Wang, Yuxia</creatorcontrib><creatorcontrib>Shirakawa, Ryutaro</creatorcontrib><creatorcontrib>Horiuchi, Hisanori</creatorcontrib><title>Ral GTPase promotes metastasis of pancreatic ductal adenocarcinoma via elevation of TGF-β1 production</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Pancreatic ductal adenocarcinoma (PDAC), caused by activating mutations in K-Ras, is an aggressive malignancy due to its early invasion and metastasis. Ral GTPases are activated downstream of Ras and play a crucial role in the development and progression of PDAC. However, the underlying mechanisms remain unclear. In this study, we investigated the mechanism of Ral-induced invasion and metastasis of PDAC cells using RalGAPβ-deficient PDAC cells with highly activated Ral GTPases. Array analysis and ELISA revealed increased expression and secretion of TGF-β1 in RalGAPβ-deficient PDAC cells compared to control cells. Blockade of TGF-β1 signaling suppressed RalGAPβ deficiency-enhanced migration and invasion in vitro and metastasis in vivo to levels similar to controls. Phosphorylation of c-Jun N-terminal kinase, a repressor of TGF-β1 expression, was decreased by RalGAPβ deficiency. These results indicate that Ral contributes to invasion and metastasis of PDAC cells by elevating autocrine TGF-β1 signaling at least in part by decreasing c-Jun N-terminal kinase activity.</description><subject>Animals</subject><subject>Carcinoma, Pancreatic Ductal - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>GTP Phosphohydrolases - metabolism</subject><subject>Humans</subject><subject>metastasis</subject><subject>Mice</subject><subject>Neoplasm Metastasis</subject><subject>pancreatic ductal adenocarcinoma</subject><subject>Pancreatic Neoplasms</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Ral GTPase</subject><subject>RalGAP</subject><subject>TGF-β1</subject><subject>Transforming Growth Factor beta1 - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc-KFDEQxoMo7rj6AF6kj156rKQ7_QcPIos7CguKjOAt1FQqmqG7MyY9A_taPojPZJpZF70YAiGV3_elqE-I5xLWEmTzar_e72itQFX5Xre6fiBWErqqrLT8-lCsAJQse6W7C_EkpT3kVffysbioWimbFuqVcJ9xKDbbT5i4OMQwhplTMfKMKW-fiuCKA04UGWdPhT3SnHm0PAXCSH4KIxYnjwUPfMpImBbFdnNd_vopF8NFkatPxSOHQ-Jnd-el-HL9bnv1vrz5uPlw9fampKpp67IGcM46t9PcUNei07pB1VvS3ClJEhgcupYcEjH32tVQ7UCj1XVHYKvqUrw5-x6Ou5Et8TRHHMwh-hHjrQnozb8vk_9uvoWTkaDyHBudHV7eOcTw48hpNqNPxMOAE4djMqqDtpctqC6j8oxSDClFdvf_SDBLQGZvckBmCcicA8qaF383eK_4k0gGXp8BzmM6eY4mkeeJ2PrINBsb_H_sfwNeIaRK</recordid><startdate>20230601</startdate><enddate>20230601</enddate><creator>Cao, Mingxin</creator><creator>Li, Xinming</creator><creator>Trinh, Duc-Anh</creator><creator>Yoshimachi, Shingo</creator><creator>Goto, Kota</creator><creator>Sakata, Natsumi</creator><creator>Ishida, Masaharu</creator><creator>Ohtsuka, Hideo</creator><creator>Unno, Michiaki</creator><creator>Wang, Yuxia</creator><creator>Shirakawa, Ryutaro</creator><creator>Horiuchi, Hisanori</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><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><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-2145-6416</orcidid><orcidid>https://orcid.org/0000-0003-4315-7131</orcidid><orcidid>https://orcid.org/0000-0002-8823-6696</orcidid></search><sort><creationdate>20230601</creationdate><title>Ral GTPase promotes metastasis of pancreatic ductal adenocarcinoma via elevation of TGF-β1 production</title><author>Cao, Mingxin ; Li, Xinming ; Trinh, Duc-Anh ; Yoshimachi, Shingo ; Goto, Kota ; Sakata, Natsumi ; Ishida, Masaharu ; Ohtsuka, Hideo ; Unno, Michiaki ; Wang, Yuxia ; Shirakawa, Ryutaro ; Horiuchi, Hisanori</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3674-400ffdffb5e6c87af556a29dc5e821c10e0faf7cfaccee95f403b05ad548c0d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Carcinoma, Pancreatic Ductal - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>GTP Phosphohydrolases - metabolism</topic><topic>Humans</topic><topic>metastasis</topic><topic>Mice</topic><topic>Neoplasm Metastasis</topic><topic>pancreatic ductal adenocarcinoma</topic><topic>Pancreatic Neoplasms</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Ral GTPase</topic><topic>RalGAP</topic><topic>TGF-β1</topic><topic>Transforming Growth Factor beta1 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cao, Mingxin</creatorcontrib><creatorcontrib>Li, Xinming</creatorcontrib><creatorcontrib>Trinh, Duc-Anh</creatorcontrib><creatorcontrib>Yoshimachi, Shingo</creatorcontrib><creatorcontrib>Goto, Kota</creatorcontrib><creatorcontrib>Sakata, Natsumi</creatorcontrib><creatorcontrib>Ishida, Masaharu</creatorcontrib><creatorcontrib>Ohtsuka, Hideo</creatorcontrib><creatorcontrib>Unno, Michiaki</creatorcontrib><creatorcontrib>Wang, Yuxia</creatorcontrib><creatorcontrib>Shirakawa, Ryutaro</creatorcontrib><creatorcontrib>Horiuchi, Hisanori</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cao, Mingxin</au><au>Li, Xinming</au><au>Trinh, Duc-Anh</au><au>Yoshimachi, Shingo</au><au>Goto, Kota</au><au>Sakata, Natsumi</au><au>Ishida, Masaharu</au><au>Ohtsuka, Hideo</au><au>Unno, Michiaki</au><au>Wang, Yuxia</au><au>Shirakawa, Ryutaro</au><au>Horiuchi, Hisanori</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ral GTPase promotes metastasis of pancreatic ductal adenocarcinoma via elevation of TGF-β1 production</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2023-06-01</date><risdate>2023</risdate><volume>299</volume><issue>6</issue><spage>104754</spage><epage>104754</epage><pages>104754-104754</pages><artnum>104754</artnum><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Pancreatic ductal adenocarcinoma (PDAC), caused by activating mutations in K-Ras, is an aggressive malignancy due to its early invasion and metastasis. Ral GTPases are activated downstream of Ras and play a crucial role in the development and progression of PDAC. However, the underlying mechanisms remain unclear. In this study, we investigated the mechanism of Ral-induced invasion and metastasis of PDAC cells using RalGAPβ-deficient PDAC cells with highly activated Ral GTPases. Array analysis and ELISA revealed increased expression and secretion of TGF-β1 in RalGAPβ-deficient PDAC cells compared to control cells. Blockade of TGF-β1 signaling suppressed RalGAPβ deficiency-enhanced migration and invasion in vitro and metastasis in vivo to levels similar to controls. Phosphorylation of c-Jun N-terminal kinase, a repressor of TGF-β1 expression, was decreased by RalGAPβ deficiency. 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| subjects | Animals Carcinoma, Pancreatic Ductal - metabolism Cell Line, Tumor Cell Movement Gene Expression Regulation, Neoplastic GTP Phosphohydrolases - metabolism Humans metastasis Mice Neoplasm Metastasis pancreatic ductal adenocarcinoma Pancreatic Neoplasms Pancreatic Neoplasms - pathology Ral GTPase RalGAP TGF-β1 Transforming Growth Factor beta1 - metabolism |
| title | Ral GTPase promotes metastasis of pancreatic ductal adenocarcinoma via elevation of TGF-β1 production |
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