Protein kinase C iota regulates pancreatic acinar-to-ductal metaplasia

Michele L. Scotti, Kristin E. Smith, Amanda M. Butler, Shelly R. Calcagno, Howard C. Crawford, Michael Leitges, Alan P Fields, Nicole R Murray

Research output: Contribution to journalArticle

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Abstract

Pancreatic acinar-to-ductal metaplasia (ADM) is associated with an increased risk of pancreatic cancer and is considered a precursor of pancreatic ductal adenocarcinoma. Transgenic expression of transforming growth factor alpha (TGF-α) or K-ras G12D in mouse pancreatic epithelium induces ADM in vivo. Protein kinase C iota (PKCι) is highly expressed in human pancreatic cancer and is required for the transformed growth and tumorigenesis of pancreatic cancer cells. In this study, PKCι expression was assessed in a mouse model of K-ras G12D-induced pancreatic ADM and pancreatic cancer. The ability of K-ras G12D to induce pancreatic ADM in explant culture, and the requirement for PKCι, was investigated. PKCι is elevated in human and mouse pancreatic ADM and intraepithelial neoplastic lesions in vivo. We demonstrate that K-ras G12D is sufficient to induce pancreatic ADM in explant culture, exhibiting many of the same morphologic and biochemical alterations observed in TGF-α-induced ADM, including a dependence on Notch activation. PKCι is highly expressed in both TGF-α- and K-ras G12D-induced pancreatic ADM and inhibition of PKCι significantly reduces TGF-α- and K-ras G12D-mediated ADM. Inhibition of PKCι suppresses K-ras G12D-induced MMP-7 expression and Notch activation, and exogenous MMP-7 restores K-ras G12D-mediated ADM in PKCι-depleted cells, implicating a K-ras G12D-PKCι-MMP-7 signaling axis that likely induces ADM through Notch activation. Our results indicate that PKCι is an early marker of pancreatic neoplasia and suggest that PKCι is a potential downstream target of K-ras G12D in pancreatic ductal metaplasia in vivo.

Original languageEnglish (US)
Article numbere30509
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - Feb 16 2012

Fingerprint

metaplasia
Metaplasia
protein kinase C
transforming growth factor alpha
Transforming Growth Factor alpha
pancreatic neoplasms
matrilysin
Pancreatic Neoplasms
Matrix Metalloproteinases
Chemical activation
protein kinase C lambda
explants
ras Proteins
mice
adenocarcinoma
lesions (animal)
carcinogenesis
Carcinogenesis
Adenocarcinoma
Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Scotti, M. L., Smith, K. E., Butler, A. M., Calcagno, S. R., Crawford, H. C., Leitges, M., ... Murray, N. R. (2012). Protein kinase C iota regulates pancreatic acinar-to-ductal metaplasia. PLoS One, 7(2), [e30509]. https://doi.org/10.1371/journal.pone.0030509

Protein kinase C iota regulates pancreatic acinar-to-ductal metaplasia. / Scotti, Michele L.; Smith, Kristin E.; Butler, Amanda M.; Calcagno, Shelly R.; Crawford, Howard C.; Leitges, Michael; Fields, Alan P; Murray, Nicole R.

In: PLoS One, Vol. 7, No. 2, e30509, 16.02.2012.

Research output: Contribution to journalArticle

Scotti, ML, Smith, KE, Butler, AM, Calcagno, SR, Crawford, HC, Leitges, M, Fields, AP & Murray, NR 2012, 'Protein kinase C iota regulates pancreatic acinar-to-ductal metaplasia', PLoS One, vol. 7, no. 2, e30509. https://doi.org/10.1371/journal.pone.0030509
Scotti ML, Smith KE, Butler AM, Calcagno SR, Crawford HC, Leitges M et al. Protein kinase C iota regulates pancreatic acinar-to-ductal metaplasia. PLoS One. 2012 Feb 16;7(2). e30509. https://doi.org/10.1371/journal.pone.0030509
Scotti, Michele L. ; Smith, Kristin E. ; Butler, Amanda M. ; Calcagno, Shelly R. ; Crawford, Howard C. ; Leitges, Michael ; Fields, Alan P ; Murray, Nicole R. / Protein kinase C iota regulates pancreatic acinar-to-ductal metaplasia. In: PLoS One. 2012 ; Vol. 7, No. 2.
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