Abstract
The limited supply of oxygen and nutrients is thought to result in rigorous selection of cells that will eventually form the tumor. Nupr1 expression pattern was analyzed in human tissue microarray (TMA) and correlated with survival time of the patient. Microarray analysis was conducted on MiaPaCa2 cells subjected to metabolic stress in Nupr1-silenced conditions. DNA repair and cell cycle-associated gene expression was confirmed by real-time quantitative PCR (qRT-PCR). Nupr1 and AURKA protective role were analyzed using RNA interference (RNAi) silencing or overexpression. DNA damage and autophagy were analyzed by Western blot analysis and immunofluorescence. We showed that both Nupr1 and HIF1α are coexpressed in human pancreatic ductal adenocarcinoma (PDAC) samples and negatively correlate with survival time. PDAC-derived cells submitted to hypoxia and/or glucose starvation induce DNA damage-dependent cell death concomitantly to the overexpression of stress protein Nupr1. Affymetrix-based transcriptoma analysis reveals that Nupr1 knockdown enhances DNA damage and alters the expression of several genes involved in DNA repair and cell-cycle progression. Expression of some of these genes is common to hypoxia and glucose starvation, such as Aurka gene, suggesting that Nupr1 overexpression counteracts the transcriptional changes occurring under metabolic stress. The molecular mechanism by which hypoxia and glucose starvation induce cell death involves autophagy-associated, but not caspase-dependent, cell death. Finally, we have found that AURKA expression is partially regulated by Nupr1 and plays a major role in this response. Our data reveal that Nupr1 is involved in a defense mechanism that promotes pancreatic cancer cell survival when exposed to metabolic stress.
Highlights
We showed that both Nupr1 and HIF1a are coexpressed in human pancreatic ductal adenocarcinoma (PDAC) samples and negatively correlate with survival time
Expression of some of these genes is common to hypoxia and glucose starvation, such as Aurka gene, suggesting that Nupr1 overexpression counteracts the transcriptional changes occurring under metabolic stress
Our data reveal that Nupr1 is involved in a defense mechanism that promotes pancreatic cancer cell survival when exposed to metabolic stress
Summary
We are beginning to unveil the genetic determinants of premalignant lesions of PDAC. PDAC arises from precursor lesions known as pancreatic intraepithelial neoplasia (PanIN) and, less frequently, from 2 types of cystic tumors, the mucinous cystic neoplasms (MCN) and the intraductal papillary mucinous neoplasms (IPMN). Recurrent genetic alterations associated with these lesions have been identified, including the mutational activation of the KRAS proto-oncogene, present in virtually all cases [1], and loss-of-function mutations of the G1 cyclin– dependent kinase inhibitor INK4A/ADP ribosylation factor (ARF; 80% of cases), the SMAD4/DPC4 (50%), and the TP53 (50%) tumor suppressor genes [2]. This research has increased our knowledge of the genetic alterations required for pancreatic cancer development. The irreversibility of these mutations and absence of drugs that would counteract their consequences has hindered the development of effective therapies
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