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

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 Kras G12D , 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 Kras G12D -expressing pancreas. Moreover, pancreasspecific deletion of Relb in a Kras G12D 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 stressrelated pathway that is required for oncogenic Kras G12D -dependent transformation of the pancreas. IntroductionPancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate and the lowest overall survival of all cancers (less than 3%-4% at 5 years). The incidence of PDAC almost equals its mortality rate and is increasing every year, with more than 38,000 predicted new cases in the United States and 65,000 in Europe. Surgery is the most effective treatment, but the mean life expectancy of the 15%-20% of patients who present with a resectable tumor is only 15-18 months (1). Even for patients eligible for surgery, aggressive metastasis often appears after operation, and survival of patients with metastatic disease is only 3-6 months (2). Chemotherapy and radiotherapy offer limited benefit for patients undergoing surgery in metastatic disease (3). Most strategies tested so far for the treatment of PDAC have consisted of using therapies that show some efficacy in other carcinomas, but none of them improved significantly the overall survival of PDAC patients. Hence, in order to develop new, efficient therapies against PDAC, future research must take into account PDAC specificities such as its remarkable resistance to cell stress, notably to the stress induced by chemotherapy and radiotherapy (4), and the preponderant presence of a fibrotic stroma, which favors tumor progression by creating a barrier against drug delivery and

Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

“…Therefore, due to their ability to regulate gene expression processes that determine cellular patterns of morphogenesis, Polycomb complexes are key regulators of cell development, maintain tissue homeostasis, and, when altered, give rise to cancer. NUPR1 plays a major role in pancreatic ductal adenocarcinoma (PDAC), because the oncogenic Kras G12D expression in the mouse pancreas is unable to promote precancerous lesions in the absence of NUPR1 expression (31,32,35). In addition, RING1B is weakly expressed in pancreatic intraepithelial neoplasias but strongly expressed in PDAC [as well as in hepatocellular carcinoma (14)].…”

“…Indeed, NUPR1 participates in the regulation of apoptosis by forming a complex with another IDP, prothymosin α (33), as well as being involved in DNA repair (34). In addition, NUPR1 plays key roles in pancreatic tumorigenesis, acting downstream of the Kras G12D oncogenes, which are critical for pancreatic carcinogenesis (35). Therefore, given the similarities in the physicochemical properties of RYBP and NUPR1 (namely, high isoelectric point, DNAbinding features, and an intrinsic disordered state), and the involvement of C-RING1B in some types of cancer, we hypothesize that this domain might also bind to NUPR1.…”

p8 attenuates the apoptosis induced by dihydroartemisinin in cancer cells through promoting autophagy

“…9 P8 participates in a wide range of biological functions in tumorigenesis, including anti-inflammatory, 10 cell cycle regulation, 11 autophagy, 12 and apoptosis inhibition. 13 Accumulating studies have shown that p8 is overexpressed in various cancer cells including pancreatic cancer, 14 colorectal carcinoma 15 and brain tumors. 16 Moreover, it has been reported that p8 is involved in the resistance of cancer cells to gemcitabine and adriamycin.…”

IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation

“…Several genetic and epigenetic factors (regulating senescence, autophagy, cell cycle, and apoptosis) may positively or negatively modulate the transforming activity of mutant KRAS in pancreatic cells, thereby modulating PanIN development. Among these factors, we recently described a novel intracellular pathway essential for KRAS transforming activity in the pancreas controlled by the pancreatitis-activated protein NUPR1 (also known as p8 or COM1), which involved RELB, but not RELA (6). We demonstrated that genetic deletion of Nupr1 in mice inhibits Kras-dependent PanIN development in a Relbdependent manner.…”

“…Consequently, pancreatic-specific deletion of Relb in a Kras G12D background resulted in delayed PanIN development. In addition, we found that disruption of this novel NUPR1-RELB transcriptional pathway affects the expression of genes encoding proteins that can serve as effectors of their function, such as immediate early response 3 (IER3) (6). Thus, efficient PanIN formation is dependent on Nupr1 and Relb expression, with likely involvement of Ier3.…”