Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis

Tewfik Hamidi, Hana Algül, Carla Eliana Cano, Maria José Sandi, Maria Inés Molejon, Marc Riemann, Ezequiel Luis Calvo, Gwen Lomberk, Jean Charles Dagorn, Falk Weih, Raul Urrutia, Roland Michael Schmid, Juan Lucio Iovanna

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic KrasG12D, we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from KrasG12D-expressing pancreas. Moreover, pancreasspecific deletion of Relb in a KrasG12D background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis. Cumulatively, these results reveal a NUPR1/RELB/IER3 stress-related pathway that is required for oncogenic KrasG12D-dependent transformation of the pancreas.

Original languageEnglish (US)
Pages (from-to)2092-2103
Number of pages12
JournalJournal of Clinical Investigation
Volume122
Issue number6
DOIs
StatePublished - Jun 1 2012

ASJC Scopus subject areas

  • Medicine(all)

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    Hamidi, T., Algül, H., Cano, C. E., Sandi, M. J., Molejon, M. I., Riemann, M., Calvo, E. L., Lomberk, G., Dagorn, J. C., Weih, F., Urrutia, R., Schmid, R. M., & Iovanna, J. L. (2012). Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis. Journal of Clinical Investigation, 122(6), 2092-2103. https://doi.org/10.1172/JCI60144