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

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.