【Advanced Science】Li Bin of Guangzhou Medical University and others have discovered a potential new mechanism to inhibit the occurrence of colorectal tumors!

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

Written by Mia

Colorectal cancer (CRC) is one of the most common malignancies in the world, with a high prevalence and a low
5-year survival rate.
Most colorectal cancer patients show overactivation of the Wnt/β-catenin pathway, which is an important target for colorectal cancer treatment
.
However, the development of low-toxicity and high-potency inhibitors for the Wnt/β-catenin signaling pathway is still ongoing
.

On October 21, 2022, Li Bin and Xu Wenwen of Guangzhou Medical University jointly published a newsletter entitled "Blockade of Nuclear β-Catenin Signaling via Direct Targeting of RanBP3 with NU2058 Induces Cell Senescence to Suppress Colorectal" in Advanced Science Tumorigenesis"
.
The study found that NU2058 could be a promising therapeutic drug capable of selectively inhibiting the proliferation
of nuclear translocation β-catenin-activated CRC cells in vivo and in vivo.

https://doi.
org/10.
1002/advs.
202202528

Research background

 01 

Colorectal cancer is the third leading cause of cancer-related death in the world, with an estimated 1.
9 million new cases and 935,000 deaths in 2020, accounting for about one-tenth
of cancer cases and related deaths.
In addition to the high morbidity, the limited choice of chemotherapy drugs is also one of the reasons for
the high mortality of patients with CRC.
There is an urgent need to develop effective and low-toxicity drugs to combat CRC
.

The Wnt/β-catenin pathway is constitutively activated in more than 90% of CRC patients due to adenomatous colon polyposis (APC) or β-catenin mutations, thereby destroying the cytoplasmic β-catenin destruction complex, resulting in nuclear translocation
of β-catenin 。 Nuclear β-catenin and transcription factor T cytokine (TCF)/lymphoid enhancer binding factor bind to some coactivators to form transcription-promoting complexes that increase transcription of Wnt-related targets, including c-Myc and cyclin D1, and promote CRC tumorigenesis
.

Therefore, the activation of nuclear β-catenin signaling is crucial for the occurrence and development of colorectal cancer, and nuclear β-catenin signaling is an important target for colorectal cancer treatment
.
However, the development of low-toxicity and high-potency inhibitors targeting the Wnt/β-catenin signaling pathway is still ongoing
.

Overview of the study

 02 

In this study, the team screened a biologically active compound library consisting of 280 small molecules to identify compounds with anticancer biological activity against two CRC cell lines: DLD1 with high nuclear transpose β-catenin expression and RKO
with low translocation β-catenin expression.
Among them, the normal colonic epithelial cell line NCM460 is also used for screening
.

The researchers found that NU2058 significantly inhibited the growth of DLD1 cells, but had no significant inhibitory effect on RKO cells and no significant toxicity to NCM460 cells, a result that aroused the researchers' interest
.
NU2058 was first identified by researchers as an inhibitor of guanine cyclin-dependent kinase (CDK) (CDK1/CDK2).

Further studies found that NU2058 selectively inhibits the proliferation
of nuclear transposition β-catenin-activated CRC cells in vivo and in vivo.
The translational significance
of NU2058 monotherapy or in combination with the chemotherapy drugs oxaliplatin and irinotecan (SN38) has been demonstrated in orthotopic tumor models and patient-derived xenograft models.
Therefore, the research team believes that NU2058 is a potential novel anti-cancer drug with low toxicity
in patients with CRC with β-catenin signaling activation.

Schematic diagram of NU2058 inhibition of tumorigenesis

Subsequently, the team combined limited hydrolase mass spectrometry (LiP-SMap) and mass spectrometry (MS) techniques to identify Ran-binding protein 3 (RanBP3) as a direct target for NU2058
.
The results showed that RanBP3 is a tumor suppressor in colorectal cancer and is associated with
patient survival.

Summary of the study

 03 

In conclusion, the results show that NU2058 selectively inhibits tumorigenesis
in vitro and colorectal cancer cells with nucleo β-catenin activation in vivo by enhancing the interaction between RanBP3 and β-catenin and interfering with nuclear transport of β-catenin.
This preclinical study supports the potential therapeutic application of NU2058 in the treatment of patients with CRC with nuclear translocation β-catenin activation as a strategy
against Wnt-driven CRC.

Resources:

https://doi.
org/10.
1002/advs.
202202528

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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