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Updated: Jul 17, 2026
Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
Published on: April 13, 2015
Antiadhesive effects of GRN163L--an oligonucleotide N3'->P5' thio-phosphoramidate targeting telomerase
Shalmica R Jackson1, Chun-Hong Zhu, Vera Paulson
1Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Abstract:
We determined previously that a novel human telomerase RNA (hTR) antagonist, GRN163L, inhibited the tumorigenic potential of A549-luciferase (A549-luc) lung cancer cells in vitro and in vivo. Further studies revealed that A549-luc cells were also morphologically altered by GRN163L. A549-luc cells treated before cell attachment with a single dose of GRN163L only weakly attached to the substrate and remained rounded, whereas control mismatch-treated cells exhibited typical epitheloid appearance and adhesion properties. These morphologic changes were independent of hTR expression and telomerase inhibition and were unrelated to telomere length. This effect is dependent on the molecular properties of the lipid moiety, the phosphorothioate backbone, and the presence of triplet-G sequences within the GRN163L structure. Altered adhesion was manifested by a 50% reduction in rapid cellular attachment and a 3-fold decrease in total cell spreading surface area. Administration of a single dose of GRN163L (15 mg/kg) at the time of cell inoculation, using an in vivo model of lung cancer metastasis, resulted in significant reductions in tumor burden at days 13, 20, and 27 of tumor progression. Thus, the potent antimetastatic effects of GRN163L may be related, in part, to the antiadhesive effects of this novel cancer therapeutic conferred via specific structural determinants and that these effects are independent of telomerase inhibition or telomere shortening.
Insights
The novel cancer therapeutic GRN163L reduces lung cancer metastasis by altering cell adhesion, independent of telomerase inhibition. This anti-adhesion effect stems from GRN163L
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- GRN163L, a human telomerase RNA (hTR) antagonist, previously inhibited lung cancer cell tumorigenicity.
- GRN163L induced morphological alterations in A549-luciferase (A549-luc) lung cancer cells.
Purpose of the Study:
- To investigate the anti-metastatic mechanisms of GRN163L beyond telomerase inhibition.
- To determine the structural basis for GRN163L's anti-adhesive effects on cancer cells.
Main Methods:
- Treatment of A549-luc cells with GRN163L before cell attachment.
- Assessment of cellular morphology, adhesion properties, and spreading.
- Evaluation of GRN163L's effect on tumor burden in an in vivo lung cancer metastasis model.
Main Results:
- GRN163L treatment resulted in reduced cellular attachment and spreading, independent of hTR expression or telomere length.
- Specific molecular properties of GRN163L, including its lipid moiety, phosphorothioate backbone, and triplet-G sequences, were critical for the anti-adhesive effect.
- A single dose of GRN163L significantly reduced tumor burden in a lung cancer metastasis model.
Conclusions:
- GRN163L exhibits potent anti-metastatic effects in lung cancer.
- These effects are partly mediated by GRN163L's ability to reduce cancer cell adhesion.
- The anti-adhesive properties are linked to specific structural features of GRN163L and are independent of telomerase inhibition.
