Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice

Ikuta, Kozo; Fukuda, Akira; Ogawa, Satoshi; Masuo, Kenji; Goto, Norihiro; Hiramatsu, Yukiko; Tsuda, Motoyuki; Kimura, Yukinobu; Matsumoto, Y; Kimura, Yuto; Maruno, Takahisa; Kanda, Keitaro; Nishi, Kiyoto; Takaori, Kyoichi; Üemoto, Shinji; Takaishi, Shigeo; Chiba, Tsutomu; Nishi, Eiichiro; Seno, Hiroshi

doi:10.1136/gutjnl-2017-315425

Cited by 7 publications

(5 citation statements)

References 46 publications

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“…showing that pancreatic deletion of NRDC in Kras G12D -driven mice promoted PDAC tumorigenesis, and considering the absence of NRDC expression in a subset of human PDAC 43 , the metastasis observed in Plk3-knockout mice might be attributed to deficient NRDC-mediated cleavage on Plk3 in PDAC cells. Our data suggest that, in addition to its reduced expression level, Plk3 in PDAC cells is more resistant to NRDCmediated cleavage into activated p41Plk3, conferring PDAC cells with apoptosis resistance, contributing to their progression towards malignancy and metastasis.…”

Section: Discussionmentioning

confidence: 91%

Nardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer

Fu,

Ling,

et al. 2024

Nat Commun

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Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism.

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Section: Discussionmentioning

confidence: 91%

Nardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer

Fu,

Ling,

et al. 2024

Nat Commun

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“…We demonstrated that deleting Plk3 in p48-cre;Kras LSL- G12D mice inhibited caspase-3 activation. Linking a study from Ikuta et al that pancreatic deletion of NRDC in Kras G12D -driven mice promoted PDAC tumorigenesis and NRDC expression is absent in a subset of human PDAC (Ikuta et al, 2019), metastasis in Plk3 knockout mice was correlated to deficient NRDC-mediated cleavage on Plk3 to induce anoikis in PDAC cells. Based on our data, in addition to reduced expression level, Plk3 in PDAC cells are more resistant to NRDC-mediated cleavage to generate activated p41Plk3, bestowing PDAC cells to develop anoikis resistance, to progress towards malignancy and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Nardilysin-Regulated Scission Mechanism Activates Polo-like Kinase 3 to Suppress the Development of Pancreatic Cancer

Fu¹,

Li²,

Li³

et al. 2022

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of apoptotic pathways. Here, we find that development of anoikis resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often reduced Plk3 expression in human PDAC. Importantly, a 41 kDa Plk3 (p41Plk3) that contained the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase Nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) was quickly removed by proteasome degradation preventing the p41Plk3 inhibition by PBD. We found that p41Plk3 is the activated form of Plk3 that regulates a feedforward mechanism to promote anoikis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn, induces expression of Plk3 and pro-apoptotic genes. These findings uncovered an NRDC-regulated post-translational mechanism (PTM) that activates Plk3, establishing a prototypic regulation by scission mechanism.

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“…Interestingly, sometimes it is difficult for clinicians and pathologists to distinguish between distal cholangiocarcinoma and pancreatic head cancer, so NRDC may play a potential role in identifying them. Moreover, there are still some reports indicating that deletion of NRDC in the mice’s pancreas dramatically leads to spontaneous chronic pancreatitis and accelerates KRAS-driven pancreatic tumorigenesis [ 19 ], demonstrating that NRDC may play a kind of tumor-suppressive function and be an essential factor in the growth in the pancreas.…”

Section: Discussionmentioning

confidence: 99%

“…NRDC has also been found in the mitochondria [ 16 ], cytoplasm [ 17 ], and nucleus [ 18 ] which suggests that it might participate in some important signaling pathways. Meanwhile, a report revealed that when NRDC is knocked out in mice, it leads to spontaneous chronic pancreatitis, diabetes, and the stimulation of pancreatic ductal adenocarcinoma initiation [ 19 ]. Hence, in order to determine the role of NRDC in pancreatic ductal adenocarcinoma, we designed an observational cohort study to determine the clinical value of NRDC.…”

Section: Introductionmentioning

confidence: 99%

Serum Nardilysin as a Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma

Xu¹,

Xiong²,

Yang³

et al. 2022

JCM

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Background: Nardilysin, (N-arginine dibasic convertase, NRDC) has been reported to play an important role in cancer progression, and is associated with tumor proliferation signals and inflammatory signals, such as tumor necrosis factor-a (TNF-a) and heparin-binding epidermal growth factor-like growth factor (HB-EGF), through the activation of disintegrin and metalloproteinase (ADAM) proteases. NRDC has recently been revealed to be involved in the tumorigenesis of various types of cancer, including intrahepatic cholangiocarcinoma, malignant cerebral infarction, esophageal squamous cell carcinoma, and gastric cancer. However, the expression profiles and biological relevance of NRDC in pancreatic ductal adenocarcinoma have rarely been reported. Methods: We analyzed the NRDC expression profile in pancreatic ductal adenocarcinoma by enzyme-linked immunosorbent assay (ELISA) and identified NRDC as a circulating biomarker in the serum of 112 pancreatic ductal adenocarcinoma patients. The diagnostic value of NRDC was analyzed by the area under the curve (AUC) and the receiver operating characteristic (ROC) test. Results: Our results demonstrated that the clinical prognosis significance of NRDC with the clinical characteristics in pancreatic ductal adenocarcinoma (PDAC). NRDC was notably decreased in PDAC patient serum compared with the control group (p < 0.001). Furthermore, the present study found that the NRDC expression level was correlated with T grade (p < 0.001), metastasis(p < 0.001), differentiation(p < 0.001), and TNM stage (p = 0.011). Further bioinformatics analysis revealed that NRDC correlated with proliferation and migration pathways; in particular, it mediated cell-matrix adhesion-dependent activation in pancreatic ductal adenocarcinoma. Conclusions: Serum NRDC may play a useful diagnostic biomarker to evaluate the aggressive clinical features in PAAD patients.

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Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice

Abstract: Nrdc inhibits pancreatitis and suppresses PDA initiation in mice.

Cited by 7 publications

References 46 publications

Nardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer

Nardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer

Nardilysin-Regulated Scission Mechanism Activates Polo-like Kinase 3 to Suppress the Development of Pancreatic Cancer

Serum Nardilysin as a Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma

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