Nanoencapsulation of Cordycepin Induces Switching from Necroptosis to Apoptosis in Human Oral Cancer Cells (HSC-4) Through Inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 3 (RIPK3) and Autophagy Modulation

Abstract

Human oral squamous carcinoma is considered the most common oral cancer; it imposes multiple oral and dental consequences as a result of oral cancer treatment. We previously found that the nanoencapsulation of cordycepin (CS) could inhibit oral cancer cells. However, the mechanism of action was not understood. The aim of this study was to investigate the signaling pathway by which CS and encapsulated nanoparticles (NPs) activate the inhibition of cancer cell growth. We demonstrated that human oral cancer (HSC-4) cells underwent necroptosis when incubated with high concentrations of CS, but not when incubated with either low concentrations of CS or encapsulated CS NPs. High concentrations of CS-induced necroptosis of HSC-4 cells, demonstrated by a reduction in apoptotic ( BAX, Caspase-3, Caspase-8, and Caspase-9) and autophagic genes ( LC3, Atg5, and Atg12). However, low concentrations of CS significantly induced the expression of autophagic gene LC3. Interestingly, encapsulated CS NPs induced a significant increase in apoptotic genes ( P53, BAX, Caspase-3, Caspase-8, and Caspase-9), but a significant decrease in autophagic ( P62, Atg5, and Atg12) and necroptotic genes ( receptor-interacting serine/threonine-protein kinase 3 [RIPK3]) . We also found that encapsulated CS NPs enhanced the accumulation of cellular protein and decreased secreted supernatant protein levels. Moreover, encapsulated CS NPs had higher efficacy in terms of reactive oxygen species (ROS) generation-mediated inhibition of autophagy compared to nonencapsulated CS, suggesting that nanoencapsulation of CS can switch the program of HSC-4 cell death from necroptosis to apoptosis. In conclusion, HSC-4 cells have a defense strategy against CS-induced cell apoptosis, but this problem can be solved through the use of encapsulation combined with nanotechnology.

Exploring beyond Common Cell Death Pathways in Oral Cancer: A Systematic Review

“…Among the selected studies, 46 studies evaluated ferroptosis , 22 studies focused on pyroptosis [28,33,[64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83], 8 studies on necroptosis [84][85][86][87][88][89][90][91] and 5 studies on other types of cell death [92][93][94][95][96]. One study [28] explored both ferroptosis and pyroptosis, Among the selected studies, 46 studies evaluated ferroptosis , 22 studies focused on pyroptosis [28,33,[64][65][66][67][68][69][70][71][72][73]…”

Cordycepin attenuates migration and invasion of HSC-4 oral squamous carcinoma cells through autophagy-dependent FAK/Akt and MMP2/MMP9 suppression

“…MDC was used to label autophagic vacuole membranes as previously described. 24 After being incubated with serum deprivation or diluted cordycepin, HSC-4 cells were fixed with 4% paraformaldehyde, washed with PBS twice and incubated with 50 μM MDC for 10 min in the dark. The fluorescence intensity and single cell fluorescence counts were observed and measured by ImageJ.…”