PKA at a Cross-Road of Signaling Pathways Involved in the Regulation of Glioblastoma Migration and Invasion by the Neuropeptides VIP and PACAP
Glioblastoma (GBM) remains an incurable disease, mainly due to the high migration and invasion potency of GBM cells inside the brain. PI3K/Akt, Sonic Hedgehog (SHH), and PKA pathways play major regulatory roles in the progression of GBM. The vasoactive intestinal peptide (VIP) family of neuropeptide...
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| Veröffentlicht in: | Cancers 2019-01, Vol.11 (1), p.123 |
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| description | Glioblastoma (GBM) remains an incurable disease, mainly due to the high migration and invasion potency of GBM cells inside the brain. PI3K/Akt, Sonic Hedgehog (SHH), and PKA pathways play major regulatory roles in the progression of GBM. The vasoactive intestinal peptide (VIP) family of neuropeptides and their receptors, referred in this article as the "VIP-receptor system", has been reported to regulate proliferation, differentiation, and migration in a number of tumor cell types and more particularly in GBM cells. These neuropeptides are potent activators of the cAMP/PKA pathway. The present study aimed to investigate the cross-talks between the above cited signaling cascades. Regulation by VIP-related neuropeptides of GBM migration and invasion was evaluated ex vivo in rat brain slices explanted in culture. Effects of different combinations of VIP-related neuropeptides and of pharmacological and siRNA inhibitors of PKA, Akt, and of the SHH/GLI1 pathways were tested on GBM migration rat C6 and human U87 GBM cell lines using the wound-healing technique. Quantification of nuclear GLI1, phospho-Akt, and phospho-PTEN was assessed by western-immunoblotting. The VIP-receptor system agonists VIP and PACAP-38 significantly reduced C6 cells invasion in the rat brain parenchyma ex vivo, and C6 and U87 migration in vitro. A VIP-receptor system antagonist, VIP
increased C6 cell invasion in the rat brain parenchyma ex vivo, and C6 and migration in vitro. These effects on cell migration were abolished by selective inhibitors of the PI3K/Akt and of the SHH pathways. Furthermore, VIP and PACAP-38 reduced the expression of nuclear GLI1 while VIP
increased this expression. Selective inhibitors of Akt and PKA abolished VIP, PACAP-38, and VIP
effects on nuclear GLI1 expression in C6 cells. PACAP-38 induced a time-dependent inhibition of phospho-Akt expression and an increased phosphorylation of PTEN in C6 cells. All together, these data indicate that triggering the VIP-receptor system reduces migration and invasion in GBM cells through a PKA-dependent blockade of the PI3K/Akt and of the SHH/GLI1 pathways. Therefore, the VIP-receptor system displays anti-oncogenic properties in GBM cells and PKA is a central core in this process. |
| doi_str_mv | 10.3390/cancers11010123 |
| format | Article |
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increased C6 cell invasion in the rat brain parenchyma ex vivo, and C6 and migration in vitro. These effects on cell migration were abolished by selective inhibitors of the PI3K/Akt and of the SHH pathways. Furthermore, VIP and PACAP-38 reduced the expression of nuclear GLI1 while VIP
increased this expression. Selective inhibitors of Akt and PKA abolished VIP, PACAP-38, and VIP
effects on nuclear GLI1 expression in C6 cells. PACAP-38 induced a time-dependent inhibition of phospho-Akt expression and an increased phosphorylation of PTEN in C6 cells. All together, these data indicate that triggering the VIP-receptor system reduces migration and invasion in GBM cells through a PKA-dependent blockade of the PI3K/Akt and of the SHH/GLI1 pathways. Therefore, the VIP-receptor system displays anti-oncogenic properties in GBM cells and PKA is a central core in this process.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers11010123</identifier><identifier>PMID: 30669581</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Brain cancer ; Brain slice preparation ; Cancer ; Cell adhesion & migration ; Cell culture ; Cell migration ; Chemotherapy ; Clinical trials ; Gene amplification ; Glioblastoma ; Hedgehog protein ; Immunoblotting ; Kinases ; Life Sciences ; Mutation ; Neurobiology ; Neurons and Cognition ; Neuropeptides ; Parenchyma ; Patients ; Peptides ; Phosphorylation ; Pituitary adenylate cyclase-activating polypeptide ; Protein kinase A ; Proteins ; PTEN protein ; Signal transduction ; siRNA ; Stem cells ; Vasoactive agents ; Vasoactive intestinal peptide ; Wound healing</subject><ispartof>Cancers, 2019-01, Vol.11 (1), p.123</ispartof><rights>2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Attribution</rights><rights>2019 by the authors. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-de88a25749b2ca8dda256f501d594bd7501e99ab173ed473ad3de2c8c7c5afa43</citedby><cites>FETCH-LOGICAL-c455t-de88a25749b2ca8dda256f501d594bd7501e99ab173ed473ad3de2c8c7c5afa43</cites><orcidid>0000-0001-6009-7471 ; 0000-0001-8808-1738 ; 0000-0002-9375-6506</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/PMC6356933/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356933/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30669581$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02559248$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Bensalma, Souheyla</creatorcontrib><creatorcontrib>Turpault, Soumaya</creatorcontrib><creatorcontrib>Balandre, Annie-Claire</creatorcontrib><creatorcontrib>De Boisvilliers, Madryssa</creatorcontrib><creatorcontrib>Gaillard, Afsaneh</creatorcontrib><creatorcontrib>Chadéneau, Corinne</creatorcontrib><creatorcontrib>Muller, Jean-Marc</creatorcontrib><title>PKA at a Cross-Road of Signaling Pathways Involved in the Regulation of Glioblastoma Migration and Invasion by the Neuropeptides VIP and PACAP</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Glioblastoma (GBM) remains an incurable disease, mainly due to the high migration and invasion potency of GBM cells inside the brain. PI3K/Akt, Sonic Hedgehog (SHH), and PKA pathways play major regulatory roles in the progression of GBM. The vasoactive intestinal peptide (VIP) family of neuropeptides and their receptors, referred in this article as the "VIP-receptor system", has been reported to regulate proliferation, differentiation, and migration in a number of tumor cell types and more particularly in GBM cells. These neuropeptides are potent activators of the cAMP/PKA pathway. The present study aimed to investigate the cross-talks between the above cited signaling cascades. Regulation by VIP-related neuropeptides of GBM migration and invasion was evaluated ex vivo in rat brain slices explanted in culture. Effects of different combinations of VIP-related neuropeptides and of pharmacological and siRNA inhibitors of PKA, Akt, and of the SHH/GLI1 pathways were tested on GBM migration rat C6 and human U87 GBM cell lines using the wound-healing technique. Quantification of nuclear GLI1, phospho-Akt, and phospho-PTEN was assessed by western-immunoblotting. The VIP-receptor system agonists VIP and PACAP-38 significantly reduced C6 cells invasion in the rat brain parenchyma ex vivo, and C6 and U87 migration in vitro. A VIP-receptor system antagonist, VIP
increased C6 cell invasion in the rat brain parenchyma ex vivo, and C6 and migration in vitro. These effects on cell migration were abolished by selective inhibitors of the PI3K/Akt and of the SHH pathways. Furthermore, VIP and PACAP-38 reduced the expression of nuclear GLI1 while VIP
increased this expression. Selective inhibitors of Akt and PKA abolished VIP, PACAP-38, and VIP
effects on nuclear GLI1 expression in C6 cells. PACAP-38 induced a time-dependent inhibition of phospho-Akt expression and an increased phosphorylation of PTEN in C6 cells. All together, these data indicate that triggering the VIP-receptor system reduces migration and invasion in GBM cells through a PKA-dependent blockade of the PI3K/Akt and of the SHH/GLI1 pathways. Therefore, the VIP-receptor system displays anti-oncogenic properties in GBM cells and PKA is a central core in this process.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Brain cancer</subject><subject>Brain slice preparation</subject><subject>Cancer</subject><subject>Cell adhesion & migration</subject><subject>Cell culture</subject><subject>Cell migration</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Gene amplification</subject><subject>Glioblastoma</subject><subject>Hedgehog protein</subject><subject>Immunoblotting</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Mutation</subject><subject>Neurobiology</subject><subject>Neurons and Cognition</subject><subject>Neuropeptides</subject><subject>Parenchyma</subject><subject>Patients</subject><subject>Peptides</subject><subject>Phosphorylation</subject><subject>Pituitary adenylate cyclase-activating polypeptide</subject><subject>Protein kinase A</subject><subject>Proteins</subject><subject>PTEN protein</subject><subject>Signal transduction</subject><subject>siRNA</subject><subject>Stem cells</subject><subject>Vasoactive agents</subject><subject>Vasoactive intestinal peptide</subject><subject>Wound healing</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkk1v1DAQhiMEolXpmRuyxAUOae3YjpMLUrSCdsUCUfm4WpPYybrK2oudLNo_wW-u0y1VWfvgGc_zztiaSZLXBF9QWuLLFmyrfSAEx53RZ8lphkWW5nnJnj-xT5LzEG5xXJQSkYuXyQnFMcALcpr8rT9XCEYEaOFdCOmNA4Vch76b3sJgbI9qGNd_YB_Q0u7csNMKGYvGtUY3up8GGI2zs-BqMK4ZIIxuA-iL6f0hAlbNQgiz0-zvhV_15N1Wb0ejdEC_lvU9VVeLqn6VvOhgCPr84TxLfn76-GNxna6-XS0X1SptGedjqnRRQMYFK5ushUKp6OQdx0TxkjVKREuXJTREUK2YoKCo0llbtKLl0AGjZ8mHQ97t1Gy0arUdPQxy680G_F46MPL_iDVr2budzCnPS0pjgveHBOsj2XW1kvMdzjgvM1bsSGTfPRTz7vekwyg3JrR6GMBqNwWZEVGyLDYER_TtEXrrJh87ESnOBCsI5nmkLg9UO_fM6-7xBQTLeTTk0WhExZun_33k_w0CvQPatbYx</recordid><startdate>20190121</startdate><enddate>20190121</enddate><creator>Bensalma, Souheyla</creator><creator>Turpault, Soumaya</creator><creator>Balandre, Annie-Claire</creator><creator>De Boisvilliers, Madryssa</creator><creator>Gaillard, Afsaneh</creator><creator>Chadéneau, Corinne</creator><creator>Muller, Jean-Marc</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6009-7471</orcidid><orcidid>https://orcid.org/0000-0001-8808-1738</orcidid><orcidid>https://orcid.org/0000-0002-9375-6506</orcidid></search><sort><creationdate>20190121</creationdate><title>PKA at a Cross-Road of Signaling Pathways Involved in the Regulation of Glioblastoma Migration and Invasion by the Neuropeptides VIP and PACAP</title><author>Bensalma, Souheyla ; Turpault, Soumaya ; Balandre, Annie-Claire ; De Boisvilliers, Madryssa ; Gaillard, Afsaneh ; Chadéneau, Corinne ; Muller, Jean-Marc</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-de88a25749b2ca8dda256f501d594bd7501e99ab173ed473ad3de2c8c7c5afa43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Brain cancer</topic><topic>Brain slice preparation</topic><topic>Cancer</topic><topic>Cell adhesion & migration</topic><topic>Cell culture</topic><topic>Cell migration</topic><topic>Chemotherapy</topic><topic>Clinical trials</topic><topic>Gene amplification</topic><topic>Glioblastoma</topic><topic>Hedgehog protein</topic><topic>Immunoblotting</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Mutation</topic><topic>Neurobiology</topic><topic>Neurons and Cognition</topic><topic>Neuropeptides</topic><topic>Parenchyma</topic><topic>Patients</topic><topic>Peptides</topic><topic>Phosphorylation</topic><topic>Pituitary adenylate cyclase-activating polypeptide</topic><topic>Protein kinase A</topic><topic>Proteins</topic><topic>PTEN protein</topic><topic>Signal transduction</topic><topic>siRNA</topic><topic>Stem cells</topic><topic>Vasoactive agents</topic><topic>Vasoactive intestinal peptide</topic><topic>Wound healing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bensalma, Souheyla</creatorcontrib><creatorcontrib>Turpault, Soumaya</creatorcontrib><creatorcontrib>Balandre, Annie-Claire</creatorcontrib><creatorcontrib>De Boisvilliers, Madryssa</creatorcontrib><creatorcontrib>Gaillard, Afsaneh</creatorcontrib><creatorcontrib>Chadéneau, Corinne</creatorcontrib><creatorcontrib>Muller, Jean-Marc</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</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>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bensalma, Souheyla</au><au>Turpault, Soumaya</au><au>Balandre, Annie-Claire</au><au>De Boisvilliers, Madryssa</au><au>Gaillard, Afsaneh</au><au>Chadéneau, Corinne</au><au>Muller, Jean-Marc</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PKA at a Cross-Road of Signaling Pathways Involved in the Regulation of Glioblastoma Migration and Invasion by the Neuropeptides VIP and PACAP</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2019-01-21</date><risdate>2019</risdate><volume>11</volume><issue>1</issue><spage>123</spage><pages>123-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Glioblastoma (GBM) remains an incurable disease, mainly due to the high migration and invasion potency of GBM cells inside the brain. PI3K/Akt, Sonic Hedgehog (SHH), and PKA pathways play major regulatory roles in the progression of GBM. The vasoactive intestinal peptide (VIP) family of neuropeptides and their receptors, referred in this article as the "VIP-receptor system", has been reported to regulate proliferation, differentiation, and migration in a number of tumor cell types and more particularly in GBM cells. These neuropeptides are potent activators of the cAMP/PKA pathway. The present study aimed to investigate the cross-talks between the above cited signaling cascades. Regulation by VIP-related neuropeptides of GBM migration and invasion was evaluated ex vivo in rat brain slices explanted in culture. Effects of different combinations of VIP-related neuropeptides and of pharmacological and siRNA inhibitors of PKA, Akt, and of the SHH/GLI1 pathways were tested on GBM migration rat C6 and human U87 GBM cell lines using the wound-healing technique. Quantification of nuclear GLI1, phospho-Akt, and phospho-PTEN was assessed by western-immunoblotting. The VIP-receptor system agonists VIP and PACAP-38 significantly reduced C6 cells invasion in the rat brain parenchyma ex vivo, and C6 and U87 migration in vitro. A VIP-receptor system antagonist, VIP
increased C6 cell invasion in the rat brain parenchyma ex vivo, and C6 and migration in vitro. These effects on cell migration were abolished by selective inhibitors of the PI3K/Akt and of the SHH pathways. Furthermore, VIP and PACAP-38 reduced the expression of nuclear GLI1 while VIP
increased this expression. Selective inhibitors of Akt and PKA abolished VIP, PACAP-38, and VIP
effects on nuclear GLI1 expression in C6 cells. PACAP-38 induced a time-dependent inhibition of phospho-Akt expression and an increased phosphorylation of PTEN in C6 cells. All together, these data indicate that triggering the VIP-receptor system reduces migration and invasion in GBM cells through a PKA-dependent blockade of the PI3K/Akt and of the SHH/GLI1 pathways. Therefore, the VIP-receptor system displays anti-oncogenic properties in GBM cells and PKA is a central core in this process.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>30669581</pmid><doi>10.3390/cancers11010123</doi><orcidid>https://orcid.org/0000-0001-6009-7471</orcidid><orcidid>https://orcid.org/0000-0001-8808-1738</orcidid><orcidid>https://orcid.org/0000-0002-9375-6506</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancers, 2019-01, Vol.11 (1), p.123 |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central; PubMed Central Open Access |
| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Brain cancer Brain slice preparation Cancer Cell adhesion & migration Cell culture Cell migration Chemotherapy Clinical trials Gene amplification Glioblastoma Hedgehog protein Immunoblotting Kinases Life Sciences Mutation Neurobiology Neurons and Cognition Neuropeptides Parenchyma Patients Peptides Phosphorylation Pituitary adenylate cyclase-activating polypeptide Protein kinase A Proteins PTEN protein Signal transduction siRNA Stem cells Vasoactive agents Vasoactive intestinal peptide Wound healing |
| title | PKA at a Cross-Road of Signaling Pathways Involved in the Regulation of Glioblastoma Migration and Invasion by the Neuropeptides VIP and PACAP |
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