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Application of serine protease inhibitior Kazal type 1 (SPINK1) in preparation of preparations used for diagnosing or regulating cell aging and tumors

A technology of serine proteases and inhibitors, which is applied in the fields of protease inhibitor immunoglobulins with anti-peptide structure, anti-tumor drugs, and disease diagnosis, and can solve problems such as unclear regulation of tumors

Active Publication Date: 2020-05-08
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the importance of SASP in tumor biology, how it regulates tumors remains poorly understood

Method used

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  • Application of serine protease inhibitior Kazal type 1 (SPINK1) in preparation of preparations used for diagnosing or regulating cell aging and tumors
  • Application of serine protease inhibitior Kazal type 1 (SPINK1) in preparation of preparations used for diagnosing or regulating cell aging and tumors
  • Application of serine protease inhibitior Kazal type 1 (SPINK1) in preparation of preparations used for diagnosing or regulating cell aging and tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Example 1. Genotoxic drugs can induce high expression of SPINK1 in human stromal cells

[0184] Recently, the inventors have noticed that the human prostate stromal cell line PSC27 (mainly composed of fibroblasts) will produce a large number of SASP factors after being treated with cytotoxic, especially genotoxic chemotherapy drugs or ionizing radiation, and SPINK1 appears in the up-regulated expression range Among the highest group of proteins ( figure 1 ). In order to verify this phenomenon and expand the scope of research, the inventors then used a set of DNA damaging drugs, including mitoxantrone (MIT), satraplatin (SAT), gamma rays (RAD), doxorubicin (DOX) and bleomycin (BLEO) to treat stromal cells. In vitro experiments showed that the cells showed significantly increased DNA damage focus (γH2AX), increased galactosidase (SA-β-Gal) activity and decreased DNA synthesis (BrdU intercalation) ( figure 2 , 3, 4), implying the occurrence of typical cell cycle arrest...

Embodiment 2

[0187] Example 2. The expression of SPINK1 in the tumor microenvironment is significantly negatively correlated with the survival of patients after chemotherapy

[0188] The results of in vitro experiments prompted the inventors to continue thinking whether SPINK1 expression also occurs in the tumor microenvironment. The present inventors studied a cohort of patients who underwent clinical chemotherapy after being diagnosed with prostate cancer and surprisingly found that these patients generally showed a significant upregulation of SPINK1 in tumor tissue after treatment, but not before ( Figure 18 ). Consistent with the in vitro experimental data, the expression of SPINK1 in tissues is concentrated in the stromal cells around the glands rather than the epithelial cells in the glands ( Figure 18 ).

[0189] Compared with before chemotherapy, the high expression of SPINK1 in tumors after chemotherapy was characterized by a pre-established pathological detection system that ...

Embodiment 3

[0191] Example 3, the expression of SPINK1 in stromal cells is regulated by transcription factors such as NF-kB

[0192] Next, the present inventors studied the expression mechanism of SPINK1 in damaged stromal cells. As a key transcriptional machine that regulates SASP expression in mammalian cells, the NF-κB complex plays an important role in cellular senescence induced by oncogene induction or therapeutic injury. We first considered whether NF-κB mediates the expression of SPINK1 in stromal cells after DNA damage. The analysis found that there were several NF-κB binding sites in the upstream 4000bp region of SPINK1 ( Figure 34 ), and the subsequent fluorescent detection based on the reporter carrier confirmed the importance of these several sites.

[0193] Compared with the 293T or PSC27 cells in the control group, the TNF-α-stimulated or BLEO-treated experimental group showed a significantly increased transcriptional activity of the SPINK1 promoter ( Figure 35 , 36). ...

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Abstract

The invention relates to the application of a SPINK1 in preparation of preparations used for diagnosing or regulating cell aging and tumors. The invention reveals for the first time that the SPINK1 plays an important biological role in SASP phenotype and tumor microenvironment, and the SPINK1 is closely related to prognosis after chemotherapy treatment. Therefore, the SPINK1 can be used as a target for SASP phenotypic regulation research and tumor microenvironment-based anti-tumor research, as a marker for prognosis evaluation and grading of tumors after chemotherapy treatment, and as a targetfor developing drugs for inhibiting tumors.

Description

technical field [0001] The invention belongs to the field of disease diagnosis and regulation. More specifically, the invention relates to the application of serine protease inhibitor Kazal type 1 factor (SPINK1) in the preparation of diagnostic or regulatory agents for cell senescence and tumors. Background technique [0002] Cell senescence is characterized by infolding of the nuclear membrane, chromatin condensation, accumulation of lipofuscin, increase in cell volume, enlargement of the nucleus, increase in β-galactosidase activity, and secretion of various factors. Cellular senescence is triggered by one or more factors, activating downstream including p53, p16 INK4A Multiple signaling pathways including / Rb, PI3K / Akt, FoxO transcription factors and mitochondrial SIRT1. In addition to entering permanent proliferative arrest, senescent cells are often associated with many pathological features, including local inflammation. Cellular senescence occurs in damaged cells a...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K39/395A61K33/243A61K31/704A61K31/136A61P35/00C07K16/38C12N5/20C12Q1/6886G01N33/68
CPCA61K31/136A61K31/704A61K33/24A61K39/3955A61K45/06A61P35/00C07K16/38C12Q1/6886C12Q2600/158G01N33/68G01N2800/7042A61K2300/00A61K39/395
Inventor 孙宇陈斐
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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