PKCι induces differential phosphorylation of STAT3 to modify STAT3-related signaling pathways in pancreatic cancer cells
An increasing number of studies have documented atypical protein kinase C isoform ι (PKCι) as an oncoprotein playing multifaceted roles in pancreatic carcinogenesis, including sustaining the transformed growth, prohibiting apoptosis, strengthening invasiveness, facilitating autophagy, as well as pro...
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| Veröffentlicht in: | Journal of cell communication and signaling 2023-12, Vol.17 (4), p.1417-1433 |
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| container_title | Journal of cell communication and signaling |
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| creator | Wang, Junli Weng, Sijia Zhu, Yue Chen, Hongmei Pan, Jueyu Qiu, Shuoyu Liu, Yufeng Wei, Dapeng Zhu, Tongbo |
| description | An increasing number of studies have documented atypical protein kinase C isoform ι (PKCι) as an oncoprotein playing multifaceted roles in pancreatic carcinogenesis, including sustaining the transformed growth, prohibiting apoptosis, strengthening invasiveness, facilitating autophagy, as well as promoting the immunosuppressive tumor microenvironment of pancreatic tumors. In this study, we present novel evidence that PKCι overexpression increases STAT3 phosphorylation at the Y705 residue while decreasing STAT3 phosphorylation at the S727 residue in pancreatic cancer cells. We further demonstrate that STAT3 phosphorylation at Y705 and S727 residues is mutually antagonistic, and that STAT3 Y705 phosphorylation is positively related to the transcriptional activity of STAT3 in pancreatic cancer cells. Furthermore, we discover that PKCι inhibition attenuates STAT3 transcriptional activity via Y705 dephosphorylation, which appears to be resulted from enhanced phosphorylation of S727 in pancreatic cancer cells. Finally, we investigate and prove that by modulating the STAT3 activity, the PKCι inhibitor can synergistically enhance the antitumor effects of pharmacological STAT3 inhibitors or reverse the anti-apoptotic side effects incited by the MEK inhibitor, thereby posing as a prospective sensitizer in the treatment of pancreatic cancer cells.
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| doi_str_mv | 10.1007/s12079-023-00780-9 |
| format | Article |
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Graphical abstract</description><identifier>ISSN: 1873-9601</identifier><identifier>EISSN: 1873-961X</identifier><identifier>DOI: 10.1007/s12079-023-00780-9</identifier><identifier>PMID: 37548811</identifier><language>eng</language><publisher>Dordrecht: Springer Netherlands</publisher><subject>Antitumor activity ; Apoptosis ; Autophagy ; Biomedical and Life Sciences ; Biomedicine ; Carcinogenesis ; Cell Biology ; Dephosphorylation ; Differential phosphorylation ; Invasiveness ; Kinases ; Life Sciences ; MEK inhibitors ; Pancreatic cancer ; Phosphorylation ; PKCι ; Protein kinase C ; Sensitizer ; STAT3 ; Stat3 protein ; Tumor microenvironment</subject><ispartof>Journal of cell communication and signaling, 2023-12, Vol.17 (4), p.1417-1433</ispartof><rights>The International CCN Society 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>The International CCN Society</rights><rights>2023. The International CCN Society.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3988-8449b3deaae641cd14cfbeb9cd3eb09c6a5be7aac9028ec83640b17b891b2b5f3</citedby><cites>FETCH-LOGICAL-c3988-8449b3deaae641cd14cfbeb9cd3eb09c6a5be7aac9028ec83640b17b891b2b5f3</cites><orcidid>0000-0003-4539-9484</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/PMC10713918/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10713918/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37548811$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Junli</creatorcontrib><creatorcontrib>Weng, Sijia</creatorcontrib><creatorcontrib>Zhu, Yue</creatorcontrib><creatorcontrib>Chen, Hongmei</creatorcontrib><creatorcontrib>Pan, Jueyu</creatorcontrib><creatorcontrib>Qiu, Shuoyu</creatorcontrib><creatorcontrib>Liu, Yufeng</creatorcontrib><creatorcontrib>Wei, Dapeng</creatorcontrib><creatorcontrib>Zhu, Tongbo</creatorcontrib><title>PKCι induces differential phosphorylation of STAT3 to modify STAT3-related signaling pathways in pancreatic cancer cells</title><title>Journal of cell communication and signaling</title><addtitle>J. Cell Commun. Signal</addtitle><addtitle>J Cell Commun Signal</addtitle><description>An increasing number of studies have documented atypical protein kinase C isoform ι (PKCι) as an oncoprotein playing multifaceted roles in pancreatic carcinogenesis, including sustaining the transformed growth, prohibiting apoptosis, strengthening invasiveness, facilitating autophagy, as well as promoting the immunosuppressive tumor microenvironment of pancreatic tumors. In this study, we present novel evidence that PKCι overexpression increases STAT3 phosphorylation at the Y705 residue while decreasing STAT3 phosphorylation at the S727 residue in pancreatic cancer cells. We further demonstrate that STAT3 phosphorylation at Y705 and S727 residues is mutually antagonistic, and that STAT3 Y705 phosphorylation is positively related to the transcriptional activity of STAT3 in pancreatic cancer cells. Furthermore, we discover that PKCι inhibition attenuates STAT3 transcriptional activity via Y705 dephosphorylation, which appears to be resulted from enhanced phosphorylation of S727 in pancreatic cancer cells. Finally, we investigate and prove that by modulating the STAT3 activity, the PKCι inhibitor can synergistically enhance the antitumor effects of pharmacological STAT3 inhibitors or reverse the anti-apoptotic side effects incited by the MEK inhibitor, thereby posing as a prospective sensitizer in the treatment of pancreatic cancer cells.
Graphical abstract</description><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Autophagy</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Carcinogenesis</subject><subject>Cell Biology</subject><subject>Dephosphorylation</subject><subject>Differential phosphorylation</subject><subject>Invasiveness</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>MEK inhibitors</subject><subject>Pancreatic cancer</subject><subject>Phosphorylation</subject><subject>PKCι</subject><subject>Protein kinase C</subject><subject>Sensitizer</subject><subject>STAT3</subject><subject>Stat3 protein</subject><subject>Tumor microenvironment</subject><issn>1873-9601</issn><issn>1873-961X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNqNkU2O1DAQhSMEYn7gAiyQJTZsAq44iW2xQEM0A4iRQJpGYmfZTqXbo3Tc2GlGORqX4Ew4ZGh-FoiF5Sr5q6dXfln2COgzoJQ_j1BQLnNasDy1gubyTnYMgrNc1vDp7qGmcJSdxHhNacWrAu5nR4xXpRAAx9n04V3z7StxQ7u3GEnrug4DDqPTPdltfEwnTL0enR-I78jV6mzFyOjJ1id0Wvo8YCKwJdGtB927YU12etzc6Ckm4VQPNmCSsMSmEgOx2PfxQXav033Eh7f3afbx4nzVvMkv379-25xd5pZJIXJRltKwFrXGugTbQmk7g0balqGh0ta6Msi1tpIWAq1gdUkNcCMkmMJUHTvNXi66u73ZYmvTckH3ahfcVodJee3Uny-D26i1_6KAcmASRFJ4eqsQ_Oc9xlFtXZx30AP6fVSFKDkry5LN6JO_0Gu_D-lTEiUprTkFgEQVC2WDjzFgd3ADVM3RqiValaJVP6JVMg09_n2Pw8jPLBPwYgFuXI_Tf0iqprliry7mbnbOlumYBoc1hl_O_2HqO9vnw5U</recordid><startdate>202312</startdate><enddate>202312</enddate><creator>Wang, Junli</creator><creator>Weng, Sijia</creator><creator>Zhu, Yue</creator><creator>Chen, Hongmei</creator><creator>Pan, Jueyu</creator><creator>Qiu, Shuoyu</creator><creator>Liu, Yufeng</creator><creator>Wei, Dapeng</creator><creator>Zhu, Tongbo</creator><general>Springer Netherlands</general><general>John Wiley & Sons, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4539-9484</orcidid></search><sort><creationdate>202312</creationdate><title>PKCι induces differential phosphorylation of STAT3 to modify STAT3-related signaling pathways in pancreatic cancer cells</title><author>Wang, Junli ; Weng, Sijia ; Zhu, Yue ; Chen, Hongmei ; Pan, Jueyu ; Qiu, Shuoyu ; Liu, Yufeng ; Wei, Dapeng ; Zhu, Tongbo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3988-8449b3deaae641cd14cfbeb9cd3eb09c6a5be7aac9028ec83640b17b891b2b5f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>Autophagy</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Carcinogenesis</topic><topic>Cell Biology</topic><topic>Dephosphorylation</topic><topic>Differential phosphorylation</topic><topic>Invasiveness</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>MEK inhibitors</topic><topic>Pancreatic cancer</topic><topic>Phosphorylation</topic><topic>PKCι</topic><topic>Protein kinase C</topic><topic>Sensitizer</topic><topic>STAT3</topic><topic>Stat3 protein</topic><topic>Tumor microenvironment</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Junli</creatorcontrib><creatorcontrib>Weng, Sijia</creatorcontrib><creatorcontrib>Zhu, Yue</creatorcontrib><creatorcontrib>Chen, Hongmei</creatorcontrib><creatorcontrib>Pan, Jueyu</creatorcontrib><creatorcontrib>Qiu, Shuoyu</creatorcontrib><creatorcontrib>Liu, Yufeng</creatorcontrib><creatorcontrib>Wei, Dapeng</creatorcontrib><creatorcontrib>Zhu, Tongbo</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cell communication and signaling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Junli</au><au>Weng, Sijia</au><au>Zhu, Yue</au><au>Chen, Hongmei</au><au>Pan, Jueyu</au><au>Qiu, Shuoyu</au><au>Liu, Yufeng</au><au>Wei, Dapeng</au><au>Zhu, Tongbo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PKCι induces differential phosphorylation of STAT3 to modify STAT3-related signaling pathways in pancreatic cancer cells</atitle><jtitle>Journal of cell communication and signaling</jtitle><stitle>J. Cell Commun. Signal</stitle><addtitle>J Cell Commun Signal</addtitle><date>2023-12</date><risdate>2023</risdate><volume>17</volume><issue>4</issue><spage>1417</spage><epage>1433</epage><pages>1417-1433</pages><issn>1873-9601</issn><eissn>1873-961X</eissn><abstract>An increasing number of studies have documented atypical protein kinase C isoform ι (PKCι) as an oncoprotein playing multifaceted roles in pancreatic carcinogenesis, including sustaining the transformed growth, prohibiting apoptosis, strengthening invasiveness, facilitating autophagy, as well as promoting the immunosuppressive tumor microenvironment of pancreatic tumors. In this study, we present novel evidence that PKCι overexpression increases STAT3 phosphorylation at the Y705 residue while decreasing STAT3 phosphorylation at the S727 residue in pancreatic cancer cells. We further demonstrate that STAT3 phosphorylation at Y705 and S727 residues is mutually antagonistic, and that STAT3 Y705 phosphorylation is positively related to the transcriptional activity of STAT3 in pancreatic cancer cells. Furthermore, we discover that PKCι inhibition attenuates STAT3 transcriptional activity via Y705 dephosphorylation, which appears to be resulted from enhanced phosphorylation of S727 in pancreatic cancer cells. Finally, we investigate and prove that by modulating the STAT3 activity, the PKCι inhibitor can synergistically enhance the antitumor effects of pharmacological STAT3 inhibitors or reverse the anti-apoptotic side effects incited by the MEK inhibitor, thereby posing as a prospective sensitizer in the treatment of pancreatic cancer cells.
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| subjects | Antitumor activity Apoptosis Autophagy Biomedical and Life Sciences Biomedicine Carcinogenesis Cell Biology Dephosphorylation Differential phosphorylation Invasiveness Kinases Life Sciences MEK inhibitors Pancreatic cancer Phosphorylation PKCι Protein kinase C Sensitizer STAT3 Stat3 protein Tumor microenvironment |
| title | PKCι induces differential phosphorylation of STAT3 to modify STAT3-related signaling pathways in pancreatic cancer cells |
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