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This article is the original of the translational medicine network, please indicate the source when reprinting
Author: Sophia
Introduction: Pancreatic cancer is one of the common malignant tumors of the digestive tract, and it is known
as the "king of cancer" in the field of tumors.
According to the journal The Lancet, the five-year survival rate after the diagnosis of pancreatic cancer is about 10%, which is one of the worst malignancies in
the prognosis.
Pancreatic cancer has insidious and atypical clinical symptoms, and is a gastrointestinal malignancy that is difficult to diagnose and treat, and about 90% of them are ductal adenocarcinoma
originating in the epithelial epithelium.
Its morbidity and mortality have increased significantly in
recent years.
The early diagnosis rate of pancreatic cancer is not high, the surgical mortality rate is high, and the cure rate is very low
.
The incidence of the disease is higher in men than in women, the ratio of men to women is 1.
5 to 2:1, and the incidence of men is far more common than that of premenopausal women, and the incidence of postmenopausal women is similar
to that of men.
The difficulty of diagnosis and treatment of pancreatic cancer is mainly due to its insidious onset and rapid
metastasis.
On September 15, Yang Caiguang's team from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences and the Center for Chemical Biology Research of the Hangzhou Advanced Research Institute of the University of Chinese Academy of Sciences published a report in Cell Chemical Biology entitled "Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic.
" ductal adenocarcinoma" research paper
.
The study reports a class of new skeleton ClpP small molecule agonists and validates that abnormal activation of ClpP disrupting mitochondrial proteome homeostasis is a worthwhile pancreatic cancer treatment strategy
.
_msthash="251140" _msttexthash="325104">Research overview
01
Mitochondrial caseinlytic protease P (ClpP) is a candidate target for the treatment of leukemia; However, the effects of ClpP regulation on solid tumors have not been fully explored
.
Over the course of the study, the researchers discovered a potent ClpP activator with therapeutic potential
for pancreatic ductal adenocarcinoma (PDAC).
The study found
02
Based on data analysis, the researchers found that high expression of CLPP gene was positively correlated with the prognosis of pancreatic cancer patients, and the abundance of ClpP protein in pancreatic cancer tissues was significantly higher
than that of normal tissues.
Both the cell level and animal model studies based on genetic manipulation have shown that the enhancement of ClpP hydrolytic activity significantly inhibits the proliferation and tumorigenesis of pancreatic cancer cells, which indicates the feasibility
of ClpP activity excitatory anti-pancreatic cancer.
High-throughput screening combined with synthetic optimization to obtain a new skeleton of ClpP agonist ZG111, activated ClpP proteolytic enzyme function in pancreatic cancer cells of different KRAS genotypes, intervened in mitochondrial respiratory chain complex homeostasis, and indirectly inhibited the proliferation
of OXPHOS function anti-pancreatic cancer cells.
ZG111 has a good antitumor effect
on xenografted pancreatic cancer models with different KRAS genetic backgrounds.
Research implications
03
As the "energy factory" of cells, mitochondria are important sites for
various biochemical reactions such as oxidative phosphorylation (OXPHOS) and the tricarboxylic acid cycle within cells.
Currently, inhibiting respiratory chain complex intervention in OXPHOS function is an emerging tumor treatment strategy
.
The human serine hydrolase ClpP is strictly positioned in the mitochondrial matrix, timely clears the wrong or abnormal proteins in the mitochondria due to stress pressure, etc.
, and plays an important function
in maintaining the homeostasis of mitochondrial proteins.
Functional disorders of ClpP cause homeostasis disorders of respiratory chain complexes, inhibit OXPHOS function, cause proteinotoxic stress and cell death
.
Resources:
_msthash="251840" _msttexthash="3046602"> _msthash="251841" _msttexthash="1827254">https://baike.
Note: This article is intended to introduce medical research advances and cannot be used as a reference for
treatment options.
For health guidance, please visit a regular hospital
.
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