Autophagic Cell Death of Pancreatic Acinar Cells in Serine Protease Inhibitor Kazal Type 3—Deficient Mice

Ohmuraya, Masaki; Hirota, Masahiko; Araki, Masatake; Mizushima, Noboru; Matsui, Makoto; Mizumoto, Takao; Haruna, Kyoko; Kume, Shoen; Takeya, Motohiro; Ogawa, Michio; Araki, Kimi; Yamamura, Ken‐ichi

doi:10.1053/j.gastro.2005.05.057

Cited by 52 publications

(67 citation statements)

References 40 publications

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“…1B). Interestingly this hydra Kazal1(-) cellular phenotype appears very similar to that detected in exocrine pancreas of Spink3 -/-newborn mice 7 and humans suffering from chronic pancreatitis, linked in some cases to SPINK1 mutations. 8,9 In both species, a dramatic autophagy of pancreatic cells was reported.…”

Section: In Homeostatic Conditions a Tight Control Of Autophagy Is Rsupporting

confidence: 63%

Autophagy and Self-Preservation: A Step Ahead from Cell Plasticity?

Galliot¹

2006

Autophagy

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Silencing the SPINK-related gene Kazal1 in hydra gland cells induces an excessive autophagy of both gland and digestive cells, leading to animal death. Moreover, during regeneration, autophagosomes are immediately detected in regenerating tips, where Kazal1 expression is lowered. When Kazal1 is completely silenced, hydra no longer survive the amputation stress (Chera S, de Rosa R, Miljkovic-Licina M, Dobretz K, Ghila L, Kaloulis K, Galliot B. Silencing of the hydra serine protease inhibitor Kazal1 gene mimics the human Spink1 pancreatic phenotype. J Cell Sci 2006; 119:846-57). These results highlight the essential digestive and cytoprotective functions played by Kazal1 in hydra. In mammals, autophagy of exocrine pancreatic cells is also induced upon SPINK1/ Spink3 inactivation, whereas Spink3 is activated in injured pancreatic cells. Hence SPINKs, by preventing an excessive autophagy, appear to act as key players of the stress-induced self-preservation program. In hydra, this program is a prerequisite to the early cellular transition, whereby digestive cells of the regenerating tips transform into a head-organizer center. Enhancing the self-preservation program in injured tissues might therefore be the condition for unmasking their potential cell and/or developmental plasticity. HYDRA, A MODEL SYSTEM FOR DUODENAL DIGESTION AND REGENERATIONHydra is a freshwater cnidarian, made up of two cell layers, the ectoderm and the endoderm, separated by an extracellular matrix named mesoglea. This animal exhibits a tube shape, mostly a gastric cavity limited by a single opening at the top, the mouth, circled by a ring of tentacles, forming together the head region. At the other end, the basal disk secretes mucous to attach to the substratum (Fig. 1A). Hence cnidarian polyps display an oral-aboral polarity, with differentiated tissues and structures at the extremities, including a sophisticated neuromuscular system, but no organs as recognized in bilaterians.The digestive function requires the cooperation of gland cells and endodermal epithelial cells (also named digestive cells) of the gastric cavity. The gland cells, packed with secretory granules full of zymogens, display a cellular organization very similar to that of the vertebrate exocrine pancreatic cells and the proteases they release in the gastric cavity participate in the enzymatic digestion. Hence, hydra gland cells are considered as "pancreatic cells." 1 Beside its physiology, hydra provides a unique model to investigate cell and developmental plasticity. 2,3 Upon regular feeding, hydra continuously reproduce asexually through budding; after amputation they regenerate the missing part of their body in few days; after dissociation of their tissues, they can reaggregate and regenerate. The molecular work carried out over the last 15 years, showed a tremendously high level of conservation between hydra and mammalian genes 3-5 supporting the paradigmatic value of this simple animal.

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Section: In Homeostatic Conditions a Tight Control Of Autophagy Is Rsupporting

confidence: 63%

Autophagy and Self-Preservation: A Step Ahead from Cell Plasticity?

Galliot¹

2006

Autophagy

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“…In contrast, Fukuoka et al (31) reported that SPINK1 competed with mouse EGF for binding to EGFR on NIH 3T3 fibroblasts. We showed previously that excessive autophagy (cellular self-digestion) is induced in pancreatic acinar cells deficient in Spink3 (5). Interestingly, residual duct-like cells in the tubular complexes of the pancreas showed no sign of acinar cell regeneration in spite of the expression of EGFR.…”

Section: Introductionmentioning

confidence: 86%

“…Tumor-associated trypsin inhibitor was initially isolated from the urine of a patient with ovarian cancer (2) and was later found to be identical to SPINK1 (3). The role of SPINK1 has been postulated to be the prevention of inadvertent proteolysis in the pancreas caused by intra-acinar premature activation of trypsinogen (4)(5)(6). However, considerable amounts of SPINK1 were detected in many extrapancreatic tissues, including the stomach, colon, small intestine, liver, lung, kidney, and ovary (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Serine Protease Inhibitor Kazal Type 1 Promotes Proliferation of Pancreatic Cancer Cells through the Epidermal Growth Factor Receptor

Ozaki

Ohmuraya

Hirota

et al. 2009

Molecular Cancer Research

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Serine protease inhibitor, Kazal type 1 (SPINK1) is expressed not only in normal human pancreatic acinar cells but also in a variety of pancreatic ductal neoplasms. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, we hypothesized that SPINK1 binds to EGF receptor (EGFR) to activate its downstream signaling. We first showed that SPINK1 induced proliferation of NIH 3T3 cells and pancreatic cancer cell lines. We showed that SPINK1 coprecipitated with EGFR in an immunoprecipitation experiment and that the binding affinity of SPINK1 to EGFR was about half of that of EGF using quartz-crystal microbalance (QCM) technique. As expected, EGFR and its downstream molecules, signal transducer and activator of transcription 3, v-Akt murine thymoma viral oncogene homologue, and extracellular signal-regulated kinase 1/2, were phosphorylated by SPINK1 as well as EGF. To determine which pathway is the most important for cell growth, we further analyzed the effect of inhibitors. Growth stimulation by EGF or SPINK1 was completely inhibited by EGFR and mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase inhibitor but not by Janus-activated kinase and phosphoinositide 3-kinase inhibitors. To further analyze the clinical importance of SPINK1 in the development of pancreatic cancer, we examined the expression of SPINK1 and EGFR in pancreatic tubular adenocarcinomas and pancreatic intraepithelial neoplasm. Both SPNK1 and EGFR were coexpressed not only in the early stage of cancer, PanIN-1A, but also in advanced stages. Taken together, these results suggest that SPINK1 stimulates the proliferation of pancreatic cancer cells through the EGFR/mitogen-activated protein kinase cascade. (Mol Cancer Res 2009;7(9):1572-81)

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“…2), which is also known as pancreatic secretory trypsin inhibitor and tumor-associated trypsin inhibitor (3), is mainly produced in the acinar cells of the exocrine pancreas. The role of SPINK1 is postulated to be the prevention of inadvertent proteolysis in the pancreas caused by intra-acinar premature activation of trypsinogen (4)(5)(6). However, it is known that SPINK1 is widely expressed in extrapancreatic tissues, especially in the gastrointestinal and urinary tracts (7,8), suggesting that SPINK1 has additional functions in many tissues other than the pancreas.…”

Section: Introductionmentioning

confidence: 99%

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

Ida

Ozaki

Araki

et al. 2015

Molecular Cancer Research

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Colorectal cancer is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for colorectal cancer, the details remain uncertain. Serine protease inhibitor, Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states, such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, it was hypothesized that SPINK1 functions as a growth factor for tissue repair in inflammatory states, and if prolonged, acts as a promoter for cell proliferation in cancerous tissues. Here, immunohistochemical staining for SPINK1 was observed in a high percentage of colorectal cancer patient specimens and SPINK1 induced proliferation of human colon cancer cell lines. To clarify its role in colon cancer in vivo, a mouse model exposed to the colon carcinogen azoxymethane and nongenotoxic carcinogen dextran sodium sulfate revealed that Spink3 (mouse homolog of SPINK1) is overexpressed in cancerous tissues. In Spink3 heterozygous mice, tumor multiplicity and tumor volume were significantly decreased compared with wild-type mice. These results suggest that SPINK1/Spink3 stimulates the proliferation of colon cancer cells and is involved in colorectal cancer progression.Implications: Evidence suggests that SPINK1 is an important growth factor that connects chronic inflammation and cancer.

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Autophagic Cell Death of Pancreatic Acinar Cells in Serine Protease Inhibitor Kazal Type 3—Deficient Mice

Abstract: The progressive disappearance of acinar cells in Spink3(-/-) mice was due to autophagic cell death and impaired regeneration. Thus, Spink3 has essential roles in the maintenance of integrity and regeneration of acinar cells.

Cited by 52 publications

References 40 publications

Autophagy and Self-Preservation: A Step Ahead from Cell Plasticity?

Autophagy and Self-Preservation: A Step Ahead from Cell Plasticity?

Serine Protease Inhibitor Kazal Type 1 Promotes Proliferation of Pancreatic Cancer Cells through the Epidermal Growth Factor Receptor

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

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