Abstract
Lycorine, a naturally occurring compound extracted from the Amaryllidaceae plant family, has been reported to exhibit antitumor activity in various cancer cell types. In the present study, we investigated the molecular mechanisms underlying lycorine-induced apoptosis in hepatoblastoma HepG2 cells. We found that lycorine induced mitochondria-dependent apoptosis in HepG2 cells accompanied by mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential (MMP) loss, adenosine triphosphate (ATP) depletion, Ca2+ and cytochrome c (Cyto C) release, as well as caspase activation. Furthermore, we found Rho associated coiled-coil containing protein kinase 1 (ROCK1) cleavage/activation played a critical role in lycorine-induced mitochondrial apoptosis. In addition, the ROCK inhibitor Y-27632 was employed, and we found that co-treatment with Y-27632 attenuated lycorine-induced mitochondrial injury and cell apoptosis. Meanwhile, an in vivo study revealed that lycorine inhibited tumor growth and induced apoptosis in a HepG2 xenograft mouse model in association with ROCK1 activation. Taken together, all these findings suggested that lycorine induced mitochondria-dependent apoptosis through ROCK1 activation in HepG2 cells, and this may be a theoretical basis for lycorine’s anticancer effects.
Highlights
Rho-associated protein kinase (ROCK), a well-characterized Rho effector, is reported to be involved in many cellular processes, including actin dynamics, cell adhesion and migration, apoptosis, proliferation, and metabolism (Leung et al, 1996; Matsui et al, 1996; Totsukawa et al, 2000; Shi and Wei, 2007)
HepG2 cells incubated with 20 μM lycorine were exposed to different time intervals (0, 6, 9, 12, 24, 36, and 48 h) and we found that lycorine induced cell viability inhibition in a time-dependent manner (Supplementary Figure 2; *P < 0.05, ***P < 0.001)
Our results indicated that cells treated with various concentrations of lycorine (0, 0.2, 0.5, 1, 2, 10, 20, 50, and 100 μM) for 48 h resulted in a significant decrease in cell viability in a dose-dependent manner (Figure 1B; ***P < 0.001)
Summary
Rho-associated protein kinase (ROCK), a well-characterized Rho effector, is reported to be involved in many cellular processes, including actin dynamics, cell adhesion and migration, apoptosis, proliferation, and metabolism (Leung et al, 1996; Matsui et al, 1996; Totsukawa et al, 2000; Shi and Wei, 2007). High expression of ROCK1 has been reported in several human cancers and often correlated with poor survival (Liu, 2011). Studies have reported that the inhibition of ROCK1 increases survival in various animal disease models (Whatcott et al, 2017). ROCK1 has been developed as a potential therapeutic target for diseases like neurological disorders, cardiovascular diseases, and cancers (Akagi et al, 2014; Hartmann et al, 2015; Henderson et al, 2016). Induction of apoptosis during carcinogenesis is considered to effectively attenuate the progression
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