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Targeted Degradation of Signal Transduction and Activator of Transcription 3 by Chaperone-Mediated Autophagy
Haohao Song1,2, Wenping Huang1,3, Fuhao Jia1,3
1CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China.
Abstract:
Chaperone-mediated autophagy (CMA) is a lysosomal-dependent proteolysis pathway for the degradation of cytosolic proteins. However, exploiting CMA-mediated proteolysis to degrade proteins of interest in cancer therapy has not been widely applied. In this study, we develop a CMA-targeting chimera (CMATAC) to efficiently and specifically degrade signal transduction and activator of transcription 3 (STAT3) in tumor cells. CMATAC consists of STAT3 and heat shock cognate 70 kDa protein (HSC70) targeting peptides connected by a linker. To efficiently deliver CMATACs into tumor cells, lipid nanoparticles (LNPs) are used to encapsulate CMATACs (nCMATACs) and decorated with an insulin-like growth factor 2 receptor (IGF2R) targeting peptide (InCMATACs) to achieve tumor targeting and precise delivery. The CMA pathway is activated in tumor cells by a fasting-mimicking diet (FMD). Furthermore, FMD treatment strongly enhances the cellular uptake and tumor accumulation of InCMATACs by upregulating the IGF2R expression. As a result, InCMATACs efficiently degrade STAT3 protein in both A549 and HCC827 tumor cells and inhibit tumor growths in vivo. This study demonstrates that InCMATACs can be used for selective proteolysis in cancer therapy.
Insights
We developed a novel cancer therapy using chaperone-mediated autophagy (CMA) to target and degrade STAT3 proteins in tumor cells. This approach, delivered via nanoparticles, shows promise for selective proteolysis in cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Chaperone-mediated autophagy (CMA) is a lysosomal pathway for protein degradation.
- Targeting specific proteins like STAT3 via CMA for cancer therapy is an emerging strategy.
- Current methods for exploiting CMA in cancer therapy are limited.
Purpose of the Study:
- To develop a novel therapeutic agent targeting STAT3 degradation through CMA.
- To enhance tumor-specific delivery and efficacy of the therapeutic agent.
- To investigate the combined effect of the agent and a fasting-mimicking diet (FMD) on tumor growth.
Main Methods:
- Design and synthesis of CMA-targeting chimeras (CMATACs) linking STAT3 and HSC70 targeting peptides.
- Encapsulation of CMATACs in lipid nanoparticles (LNPs) and decoration with IGF2R targeting peptides (InCMATACs).
- In vitro assessment of STAT3 degradation in tumor cells and in vivo evaluation of tumor growth inhibition.
Main Results:
- InCMATACs efficiently degraded STAT3 protein in A549 and HCC827 tumor cells.
- Fasting-mimicking diet (FMD) enhanced cellular uptake and tumor accumulation of InCMATACs by upregulating IGF2R.
- InCMATACs significantly inhibited tumor growth in vivo.
Conclusions:
- InCMATACs represent a promising strategy for STAT3 degradation via CMA in cancer therapy.
- The combination of InCMATACs and FMD enhances therapeutic efficacy.
- This approach offers a novel pathway for selective proteolysis in treating cancer.
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