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Published on: July 21, 2018
Recombinant adenoviruses expressing dominant negative insulin-like growth factor-I receptor demonstrate antitumor
Choon-Taek Lee1, Kyung-Ho Park, Yasushi Adachi
1Department of Internal Medicine, Seoul National University College of Medicine, South Korea.
Abstract:
The continuous growth of tumors depends on the altered regulation of the cell cycle, which is in turn modulated by signals from growth factors and their receptors. Blockade of insulin-like growth factor (IGF)-I and IGF-IR by antisense or dominant negative plasmid transfection can suppress tumorigenicity and induce regression of established tumors. We have constructed two recombinant adenoviruses: an adenovirus expressing truncated IGF-IR (ad-IGF-IR/950) with an engineered stop codon at amino acid residue 950, and an adenovirus expressing the soluble extracellular domain of IGF-IR (ad-IGF-IR/482) with an engineered stop codon at amino acid residue 482. Ad-IGF-IR/950 produces a defective receptor with an intact alpha subunit and a defective beta subunit lacking the tyrosine kinase domain. Dominant negative inhibition results from competition of the defective receptor with normal IGF-IR subunits, or the competition with normal IGF-IR for ligand by the soluble receptor. We were able to show here that ad-IGF-IR/950 induced the increased expression of IGF-IR on the cell surface and ad-IGF-IR/482 induced the secretion of the soluble fragment of IGF-IR. The transduction of both ad-IGF-IR/950 and ad-IGF-IR/482 could blunt the growth-stimulatory effect of IGF-I on human lung cancer cell lines. Both ad-IGF-IR/950 and ad-IGF-IR/482 effectively blocked IGF-I-induced Akt kinase activation. Intratumoral injection of ad-IGF-IR/482 virus showed significant growth suppression in established lung cancer xenografts. These findings suggest that these ad-IGF-IR/dn (950, 482) have the potential to be effective and practical cancer gene therapy strategies.
Insights
Recombinant adenoviruses targeting insulin-like growth factor-I receptor (IGF-IR) suppressed lung cancer growth. These gene therapies show potential for effective cancer treatment by blocking tumor cell proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Tumor growth relies on cell cycle regulation influenced by growth factors like insulin-like growth factor-I (IGF-I).
- Blocking IGF-I signaling via IGF-I receptor (IGF-IR) can inhibit tumor growth and induce regression.
Purpose of the Study:
- To construct and evaluate recombinant adenoviruses expressing dominant-negative IGF-IR variants for cancer gene therapy.
- To assess the efficacy of these adenoviruses in blocking IGF-I signaling and suppressing lung cancer growth.
Main Methods:
- Construction of two recombinant adenoviruses: ad-IGF-IR/950 (truncated receptor) and ad-IGF-IR/482 (soluble extracellular domain).
- Assessment of IGF-IR expression, soluble fragment secretion, and inhibition of IGF-I-induced signaling pathways (e.g., Akt kinase).
- Evaluation of tumor growth suppression in human lung cancer cell lines and established lung cancer xenografts.
Main Results:
- ad-IGF-IR/950 increased cell surface IGF-IR expression; ad-IGF-IR/482 secreted soluble IGF-IR.
- Both adenoviruses blunted IGF-I's growth-stimulatory effects on lung cancer cells and blocked IGF-I-induced Akt activation.
- Intratumoral injection of ad-IGF-IR/482 significantly suppressed established lung cancer xenograft growth.
Conclusions:
- Recombinant adenoviruses expressing dominant-negative IGF-IR variants (ad-IGF-IR/950 and ad-IGF-IR/482) effectively inhibit IGF-I signaling.
- These adenoviruses demonstrate potential as practical and effective gene therapy strategies for lung cancer.
