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Targeting PABPC1: A therapeutic strategy of natural Ganoderma meroterpenoid LZ22 against triple-negative breast
Dan Cai1, Yan-Yi Chen1, Hong Hu2
1Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, MarshallLaboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China.
Abstract:
Triple-negative breast cancer (TNBC) is characterized by marked heterogeneity and is associated with a high recurrence risk. Current therapeutic approaches for TNBC remain heavily reliant on chemotherapy, with limited treatment options available. PABPC1, a highly conserved member of the poly(A)-binding protein family, plays a critical role in regulating mRNA stability and translation. Aberrant expression of PABPC1 in various cancers suggests its potential involvement in TNBC pathogenesis. In this study, we demonstrated that LZ22 a natural Ganoderma meroterpenoid, effectively inhibits the proliferation of TNBC cells. Using a chemical proteomics strategy, we identified PABPC1 as a key target mediating LZ22's anti-TNBC activity. It has been confirmed that natural meroterpenoid significantly regulate the PABPC1 downstream signaling pathway, thereby downregulating the expression of pathway-related proteins such as CDK14 and NR4A3. Furthermore, through structural optimization of LZ22 guided by molecular docking, we identified a derivative (LZ22-4) with enhanced anti-tumor proliferative activity. These findings not only identify PABPC1 as a valuable therapeutic target for TNBC but also provide new opportunities and novel insights for advancing anti-TNBC drug development with LZ22 as a potential drug leading compound.
Insights
A natural Ganoderma meroterpenoid, LZ22, inhibits triple-negative breast cancer (TNBC) cell proliferation by targeting PABPC1. Structural optimization yielded LZ22-4 with enhanced anti-tumor activity, offering new therapeutic avenues for TNBC.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) presents significant heterogeneity and a high recurrence rate.
- Current TNBC treatments primarily rely on chemotherapy, with limited therapeutic options.
- Poly(A)-binding protein C1 (PABPC1) is crucial for mRNA regulation and its aberrant expression is implicated in various cancers.
Purpose of the Study:
- To investigate the anti-TNBC effects of LZ22, a natural Ganoderma meroterpenoid.
- To identify the molecular target of LZ22 responsible for its anti-TNBC activity.
- To explore the therapeutic potential of LZ22 and its derivatives for TNBC treatment.
Main Methods:
- Chemical proteomics to identify LZ22's molecular target.
- Analysis of PABPC1 downstream signaling pathways.
- Molecular docking for structural optimization of LZ22.
- Cell proliferation assays to evaluate anti-tumor activity.
Main Results:
- LZ22 demonstrated significant inhibition of TNBC cell proliferation.
- PABPC1 was identified as a key mediator of LZ22's anti-TNBC effects.
- LZ22 was found to downregulate PABPC1 downstream signaling, including CDK14 and NR4A3 expression.
- A derivative, LZ22-4, exhibited enhanced anti-tumor proliferative activity compared to LZ22.
Conclusions:
- PABPC1 is a promising therapeutic target for TNBC.
- LZ22 is a potential lead compound for developing novel anti-TNBC drugs.
- Structural optimization of LZ22 can enhance its anti-tumor efficacy, offering new insights for drug development.
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