SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells

Abstract

BackgroundA natural compound Jaspine B and its derivative possess potential anti-cancer activities; However, little is known about the underlying mechanism. Here, the role of a new autophagy inducer Jaspine B derivative C-2 in suppressing bladder cancer cells was researched in vitro and in vivo.MethodsThe underlying mechanisms and anticancer effect of C-2 in bladder cancer cells were investigated by MTT, western blotting, immunoprecipitation and immunofluorescence assays. The key signaling components were investigated by using pharmacological inhibitors or specific siRNAs. In vivo, we designed a C-2 and SP600125 combination experiment to verify the effectiveness of compound.ResultsC-2 exhibits cytotoxic effect on bladder cancer cells, and JNK activated by C-2 triggers autophagy and up-regulates SQSTM1/p62 proteins, contributing to activation of Nrf2 pathway. Utilization of JNK inhibitor SP600125 or knockdown of JNK by siRNA potentiate the cytotoxicity of C-2 through down-regulation of p62 and LC3II proteins and up-regulation of active-Caspase3 proteins, enhance the cell death effect, facilitating the switch from autophagy to apoptosis. In vivo study, C-2 suppresses tumor growth in a xenograft mouse model of EJ cells without observed toxicity. Combined treatment with SP600125 further enhances tumor inhibition of C-2 associated with enhanced activation of caspase3 and reduction of autophagy.ConclusionsIt reveals a series of molecular mechanisms about SP600125 potentiate the cytotoxicity and tumor inhibition of C-2 in bladder cancer cells through promoting C-2-induced apoptosis, expecting it provides research basis and theoretical support for new drugs development.

β-Caryophyllene Inhibits Cell Proliferation through a Direct Modulation of CB2 Receptors in Glioblastoma Cells

“…Interestingly, scientific evidences described the JNK role in autophagy through Bcl-2 and Bcl-xL phosphorylation to active Beclin-1 [25]. In particular, as previously described, Bcl-2 and Beclin-1 reduction may be a direct consequence of JNK decrease [26]. Therefore, the results discussed so far support the idea that BCP may also regulate apoptosis and autophagy mechanisms not only through a direct modulation of CB2 receptors but also by JNK modulation.…”

Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy

“…Multiple agents in development in preclinical and clinical trials and even many clinical drugs have been found to trigger cytoprotective autophagy, including mTOR inhibitors, kinase inhibitors, natural products, and antiangiogenic agents (Haiyang Yu et al, 2019;Mei-Chuan Chen et al, 2019). Meanwhile, various signaling pathways and molecules have been identified in regulating drug-induced autophagy that impact the outcome of anticancer therapy, such as the PI3K-Akt-mTOR pathway, one of the main regulators of autophagy.…”

Blue-Print Autophagy in 2020: A Critical Review

“…A good example of research on a marine-derived compound as possible autophagy modulators is the investigation of jaspine B and its 2-alkylaminomethyl derivatives performed by two different groups [ 80 , 81 ]. Jaspine B is an anhydrophytosphingosine that was first found in the marine sponge Pachastrissa sp.…”

“…This speculation, however, requires further validation [ 83 ]. Nevertheless, in the following research by Yu et al (Jin group), the authors have applied a number of diverse methods to prove the autophagy-inducing activity of the most promising jaspine B derivative called C-2 in human bladder cancer cells [ 80 ]. Thus, the authors successfully demonstrated the importance of JNK and Nrf2 pathways for the C-2-induced autophagy, which seems to be cytoprotective, in bladder cancer cells.…”

“…Thus, the authors successfully demonstrated the importance of JNK and Nrf2 pathways for the C-2-induced autophagy, which seems to be cytoprotective, in bladder cancer cells. Finally, the anticancer and autophagy-inducing activity as well as the mode of action of C-2 were validated in vivo using the nude mice xenografts [ 80 ]. The rather contradictive results of these two high-quality pieces of research performed by Cingolani et al [ 81 ] and Yu et al [ 80 ] could be explained by the different models used, namely, gastric [ 77 ] and bladder cancer cells [ 80 ], as well as by the chemical difference in the original natural jaspine B [ 81 ] and its synthetic derivative C-2 [ 80 ].…”