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Published on: January 7, 2019
Tumor suppressor FUS1 signaling pathway
1Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77230-1402, USA. lji@mdanderson.org
Abstract:
FUS1 is a novel tumor suppressor gene identified in the human chromosome 3p21.3 region where allele losses and genetic alterations occur early and frequently for many human cancers. Expression of FUS1 protein is absent or reduced in the majority of lung cancers and premalignant lung lesions. Restoration of wt-FUS1 function in 3p21.3-deficient non-small cell lung carcinoma cells significantly inhibits tumor cell growth by induction of apoptosis and alteration of cell cycle kinetics. Here we present recent findings indicating that FUS1 induces apoptosis through the activation of the intrinsic mitochondrial-dependent and Apaf-1-associated pathways and inhibits the function of protein tyrosine kinases including EGFR, PDGFR, AKT, c-Abl, and c-Kit. Intravenous administration of a nanoparticle encapsulated FUS1 expression plasmid effectively delivers FUS1 to distant tumor sites and mediates an antitumor effect in orthotopic human lung cancer xenograft models. This approach is the rationale for an ongoing FUS1-nanoparticle-mediated gene delivery clinical trial for the treatment of lung cancer.
Insights
The FUS1 tumor suppressor gene, often lost in lung cancer, can inhibit tumor growth by inducing apoptosis and blocking key kinases. Nanoparticle delivery of FUS1 shows promise for lung cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- FUS1 is a tumor suppressor gene located in the 3p21.3 region, frequently altered in various cancers.
- Reduced FUS1 expression is observed in most lung cancers and premalignant lesions.
- FUS1 deficiency is linked to early genetic alterations in tumorigenesis.
Purpose of the Study:
- To investigate the role of FUS1 in lung cancer.
- To elucidate the mechanisms by which FUS1 inhibits tumor growth.
- To evaluate the therapeutic potential of FUS1 gene delivery using nanoparticles.
Main Methods:
- Restoration of wild-type FUS1 (wt-FUS1) in non-small cell lung carcinoma (NSCLC) cells.
- Analysis of apoptosis induction and cell cycle kinetics.
- Assessment of FUS1's effect on protein tyrosine kinases (EGFR, PDGFR, AKT, c-Abl, c-Kit).
- In vivo studies using nanoparticle-encapsulated FUS1 plasmid in orthotopic human lung cancer xenograft models.
Main Results:
- wt-FUS1 expression significantly inhibited NSCLC cell growth.
- FUS1 induced apoptosis via intrinsic mitochondrial and Apaf-1-associated pathways.
- FUS1 suppressed the activity of multiple protein tyrosine kinases.
- Nanoparticle-mediated FUS1 delivery demonstrated antitumor effects in vivo.
Conclusions:
- FUS1 functions as a tumor suppressor by promoting apoptosis and inhibiting key oncogenic kinases.
- FUS1 nanoparticle gene delivery is a viable strategy for treating lung cancer.
- This approach forms the basis for an ongoing clinical trial.
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