Non-small cell lung cancer (NSCLC) has been identified as a leading cause of
tumor-associated death around the world. Presently, it is necessary to find effective and safe
therapy for its treatment in clinic.
Jervine (Jer), a sterodial
alkaloid from rhizomes of Veratrum album, exhibits anti-inflammatory and anti-
cancer effects. However, its effects on
lung cancer progression are still unknown. In this study, we explored if Jer showed any influences on NSCLC development, as well as the underlying molecular mechanisms. The results showed that Jer time- and dose-dependently reduced the proliferation of NSCLC cells, along with inhibited colony formation capacity. Apoptosis was highly induced by Jer in NSCLC cells through promoting the expression of cleaved
Caspase-3. Furthermore, Jer treatment led to autophagy in
cancer cells, as evidenced by the fluorescence microscopy results and increases of LC3II. Autophagy inhibitor bafilomycinA1 (BafA1) abrogated the inhibitory effects of Jer on cell proliferation and apoptosis induction, showing that Jer triggered autophagy-mediated apoptosis in NSCLC cells. Additionally, AKT and
mammalian target of Rapamycin (mTOR) signaling pathway was highly repressed in
cancer cells. Importantly, promoting AKT activation greatly rescued the cell survival, while attenuated autophagy and apoptosis in Jer-incubated NSCLC cells, revealing that Jer-modulated autophagic cell death was through the blockage of AKT signaling. Hedgehog signaling pathway was then found to be suppressed by Jer, as proved by the decreased expression of Sonic Hedgehog (Shh), Hedgehog receptor
protein patched homolog 1 (PTCH1), smoothened (SMO) and
glioma-associated oncogene homolog 1 (Gli1) in NSCLC cells. Of note, enhancing Shh signaling dramatically diminished the stimulative effects of Jer on autophagy-mediated apoptosis in vitro, demonstrating the importance of Hedgehog signaling in Jer-regulated cell death. Moreover, Jer treatment effectively reduced
tumor growth in A549-bearing mice with few toxicity. Together, Jer may be a promising and effective therapeutic strategy for NSCLC treatment.