Effects of long-term exposure to MST-312 on lung cancer cells tumorigenesis: Role of SHH/GLI-1 axis.

Abstract

Replicative immortality is a key feature of cancer cells and it is maintained by the expression of telomerase, a promising target of novel therapies. Long-term telomerase inhibition can induce resistance, but the mechanisms underlying this process remain unclear. The Sonic hedgehog pathway (SHH) is an embryogenic pathway involved in tumorigenesis and modulates the transcription of telomerase. We evaluated the effects of long-term treatment of the telomerase inhibitor MST-312 in morphology, proliferation, resistance, and in the SHH pathway molecules expression levels in lung cancer cells. Cells treated for 12 weeks with MST-312 showed changes in morphology, such as spindle-shaped cells, and a shift in the distribution of F-ACTIN from cortical to diffuse. Treatment also significantly reduced cells' efficiency to form spheroids and their clonogenic potential, independently of the cell cycle and telomeric DNA content. Moreover, GLI-1 expression levels were significantly reduced after 12 weeks of MST-312 treatment, indicating a possible inhibition of this signaling axis in the SHH pathway, without hindering NANOG and OCT4 expression. Here, we described a novel implication of long-term treatment with MST-312 functionally and molecularly, shedding new light on the molecular mechanisms of this drug in vitro.

• Authors: Nicolas Jones Villarinho, Flavia da Cunha Vasconcelos, Luciano Mazzoccoli, Marcela Cristina da Silva Robaina, Luciana Santos Pessoa, Pablo Enrique Torres Siqueira, Raquel Ciuvalschi Maia, Diego Madureira de Oliveira, Tania Cristina Leite de Sampaio E Spohr, Giselle Faria Lopes
• Journal: Cell biology international (Cell Biol Int) Vol. 46 Issue 9 Pg. 1468-1479 (Sep 2022) ISSN: 1095-8355 [Electronic] England
• PMID: 35811464 (Publication Type: Journal Article)
• Copyright: © 2022 International Federation for Cell Biology.

Chemical References

• Benzamides
• Hedgehog Proteins
• MST 312
• SHH protein, human
• Zinc Finger Protein GLI1
• Telomerase

Topics

• Benzamides
• Carcinogenesis
• Cell Line, Tumor
• Cell Proliferation
• Hedgehog Proteins (metabolism)
• Humans
• Lung Neoplasms
• Telomerase (metabolism)
• Zinc Finger Protein GLI1 (metabolism)