【STTT】This anti-allergy drug is expected to fight cancer! Li Bin's team from Guangzhou Medical University discovered a new therapeutic target for liver cancer

This article is the original of Translational Medicine Network, please indicate the source for reprinting

Author: Mia

As the most common type of liver cancer, hepatocellular carcinoma (HCC) has a poor prognosis and is the fourth leading cause
of cancer-related death worldwide.
Despite improvements in chemotherapy in recent decades, poor patient survival is a major problem
with current cancer treatments.
Therefore, there is an urgent need to find liver cancer treatment drugs
with anti-tumor efficacy and low toxicity.

Recently, Li Bin of Guangzhou Medical University and others published a title entitled "Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression" in Signal Transduction and Targeted Therapy.
of research reports
.
This study confirms the potential of N-myristic yltransferase 1 (NMT1) as a prognostic biomarker and therapeutic target for HCC and supports the use of
desloratadine in cancer treatment.

https://doi.
org/10.
1038/s41392-022-01248-9

The low survival rate of patients with hepatocellular carcinoma needs to be improved

 01 

As the most common type of liver cancer, hepatocellular carcinoma (HCC) has a poor prognosis and is the fourth leading cause
of cancer-related death worldwide.
Although surgical excision and transplantation can be used to treat early HCC, most patients are diagnosed at an advanced stage
.
Chemotherapy has improved in recent decades, but poor survival rates for patients are a major problem
with current cancer treatments.
In addition, sorafenib and regorafenib have remarkable effects in the treatment of liver cancer, but due to the problems of drug resistance and tumor recurrence, there is still an urgent need to find liver cancer treatment drugs
with anti-tumor efficacy and low toxicity.

Drug repurposing refers to the process
of developing new uses beyond the indications of the original drug.
Drug repurposing strategies have multiple advantages over developing new drugs for specific indications; For example, the failure rate is lower, drug development takes less time, and the monetary cost is reduced
.
In this study, based on a small molecule library of 419 FDA-approved drugs, the researchers identified desloratadine as a drug
candidate for the treatment of HCC.
Deloratadine is an orally active H1 receptor antagonist commonly used to treat allergies, but scientists do not know
its potential role in cancer treatment.

Potential biomarkers and therapeutic targets for HCC

 02 

After a series of functional experiments, the researchers found that the anti-allergy drug desloratadine inhibited the proliferation
of hepatoma cell lines, cell-derived xenograft (CDX), patient-derived organoids (PDO), and patient-derived xenograft (PDX) models.
In addition, N-myristoyl transferase 1 (NMT1) was the target protein of desloratadine by drug affinity response target stability (DARTS) and surface plasmon resonance (SPR) determination
.

NMT1 is an important major enzyme
for irreversible eukaryotic lipid modification of N-myristic ylation.
NMT1 was overexpressed in a variety of cancers, and NMT1 expression was positively correlated
with poor survival.
In addition, myristic acylation refers to the covalent binding
of myristic acid to protein N-terminal glycine residues.
The dysregulation of protein myristoylation is closely related
to various cancers.
Studies have confirmed that myristoylation of the viral oncogene product PP60V-SRC plays an important role
in membrane transformation.
A growing number of studies have identified protein myristoylation as a target for anti-cancer chemotherapy drugs
.
This study is the first to analyze the role of
NMT1 in HCC.

In vivo and in vitro experiments, up-regulation of NMT1 expression promotes tumor growth, while down-regulation of NMT1 inhibits tumor growth
.
Metabolic labeling and mass spectrometry analysis showed that Visinin-like protein 3 (VILIP3) is a new substrate for the acylation modification of NMT1 proteins, and high expression of NMT1 or VILIP3 is associated with
late HCC and low survival.
Mechanistically, desloratadine binds to Asn-246 in NMT1 and inhibits its enzymatic activity, disrupting NMT1-mediated myristic myrithylation of VILIP3 protein and subsequent NFκB/Bcl-2 signaling pathway
.

In conclusion, the study found that desloratadine is a novel potential anti-cancer drug, and NMT1-mediated myristenylation contributes to the progression of HCC, which is a potential biomarker and therapeutic target for HCC
.

Research significance

 03 

In this study, the researchers provide the first evidence that VILIP3 protein is a novel catalytic substrate protein for NMT1 and that myristoylation of VILIP3 affects the stability
of its regulatory axis of activating NFκB/Bcl-2.
In HCC patients, VILIP3 overexpression was associated with low survival, and more importantly, down-regulation of VILIP3 inhibited cell proliferation and viability, suggesting that VILIP3 may be a useful biomarker and therapeutic target in HCC
.

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Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.

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