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Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42.

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Title: Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42.
Authors: Razidlo, Gina L.1,2 razidlo.gina@mayo.edu, Burton, Kevin M.2,3, Mcniven, Mark A.1,2
Source: Journal of Biological Chemistry. 7/13/2018, Vol. 293 Issue 28, p11143-11153. 11p.
Subjects: Pancreatic cancer genetics, Interleukin-6 receptors, Cancer cell migration, Guanosine triphosphatase regulation, Cancer invasiveness
Abstract: Inflammation is a major driver of tumor progression and metastasis, although the mechanisms by which proinflammatory cytokines drive metastatic invasion are unknown. Interleukin-6 (IL-6) is a potent proinflammatory cytokine that is elevated in individuals with pancreatic cancer (PDAC), is required for PDAC progression in mice, and increases tumor cell invasion in vitro. Here, we provide insights into the mechanisms by which IL-6 activates tumor cell invasion. We found that IL-6 stimulation rapidly and robustly activates the small GTPase cell division cycle 42 (CDC42) in human PDAC cells and promotes the formation of premigratory filopodia. The CDC42 activation was required for IL-6-induced invasion as blocking CDC42 activity rendered the cells insensitive to IL-6's proinvasive effects. Loss of Janus kinase 2 (JAK2) or signal transducer and activator of transcription 3 (STAT3) prevented IL-6-mediated CDC42 activation, indicating that IL-6 activates CDC42 through both JAK2 and STAT3. However, the rapid activation of CDC42 suggested that this activation may be distinct from canonical STAT3-mediated transcriptional activation. Importantly, we observed an interaction between STAT3 and IQ motif-containing GTPase-activating protein 1 (IQGAP1), a scaffolding platform that binds CDC42. STAT3 colocalized with CDC42 and IQGAP1 at the plasma membrane, suggesting cross-talk between IL-6 - mediated STAT3 signaling and CDC42 activation. These results suggest that IL-6 promotes metastatic invasion, at least partially, through CDC42 and that, along with its pleiotropic effects on tumor growth and progression, IL-6 signaling also activates proinvasive GTPase signaling, priming tumor cells for metastatic invasion. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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PubType: Academic Journal
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  Data: Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42.
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  Data: <searchLink fieldCode="AR" term="%22Razidlo%2C+Gina+L%2E%22">Razidlo, Gina L.</searchLink><relatesTo>1,2</relatesTo><i> razidlo.gina@mayo.edu</i><br /><searchLink fieldCode="AR" term="%22Burton%2C+Kevin+M%2E%22">Burton, Kevin M.</searchLink><relatesTo>2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Mcniven%2C+Mark+A%2E%22">Mcniven, Mark A.</searchLink><relatesTo>1,2</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. 7/13/2018, Vol. 293 Issue 28, p11143-11153. 11p.
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  Data: <searchLink fieldCode="DE" term="%22Pancreatic+cancer+genetics%22">Pancreatic cancer genetics</searchLink><br /><searchLink fieldCode="DE" term="%22Interleukin-6+receptors%22">Interleukin-6 receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+cell+migration%22">Cancer cell migration</searchLink><br /><searchLink fieldCode="DE" term="%22Guanosine+triphosphatase+regulation%22">Guanosine triphosphatase regulation</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+invasiveness%22">Cancer invasiveness</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Inflammation is a major driver of tumor progression and metastasis, although the mechanisms by which proinflammatory cytokines drive metastatic invasion are unknown. Interleukin-6 (IL-6) is a potent proinflammatory cytokine that is elevated in individuals with pancreatic cancer (PDAC), is required for PDAC progression in mice, and increases tumor cell invasion in vitro. Here, we provide insights into the mechanisms by which IL-6 activates tumor cell invasion. We found that IL-6 stimulation rapidly and robustly activates the small GTPase cell division cycle 42 (CDC42) in human PDAC cells and promotes the formation of premigratory filopodia. The CDC42 activation was required for IL-6-induced invasion as blocking CDC42 activity rendered the cells insensitive to IL-6's proinvasive effects. Loss of Janus kinase 2 (JAK2) or signal transducer and activator of transcription 3 (STAT3) prevented IL-6-mediated CDC42 activation, indicating that IL-6 activates CDC42 through both JAK2 and STAT3. However, the rapid activation of CDC42 suggested that this activation may be distinct from canonical STAT3-mediated transcriptional activation. Importantly, we observed an interaction between STAT3 and IQ motif-containing GTPase-activating protein 1 (IQGAP1), a scaffolding platform that binds CDC42. STAT3 colocalized with CDC42 and IQGAP1 at the plasma membrane, suggesting cross-talk between IL-6 - mediated STAT3 signaling and CDC42 activation. These results suggest that IL-6 promotes metastatic invasion, at least partially, through CDC42 and that, along with its pleiotropic effects on tumor growth and progression, IL-6 signaling also activates proinvasive GTPase signaling, priming tumor cells for metastatic invasion. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1074/jbc.RA118.003276
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        Text: English
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        PageCount: 11
        StartPage: 11143
    Subjects:
      – SubjectFull: Pancreatic cancer genetics
        Type: general
      – SubjectFull: Interleukin-6 receptors
        Type: general
      – SubjectFull: Cancer cell migration
        Type: general
      – SubjectFull: Guanosine triphosphatase regulation
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      – SubjectFull: Cancer invasiveness
        Type: general
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      – TitleFull: Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42.
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            NameFull: Razidlo, Gina L.
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            NameFull: Burton, Kevin M.
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              Text: 7/13/2018
              Type: published
              Y: 2018
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