MicroRNAs (miRNAs) are a class of noncoding RNAs that negatively regulate target messenger RNAs. In multicellular eukaryotes, numerous miRNAs perform basic cellular functions including cell proliferation, differentiation, and death. Abnormal expression of miRNAs weakens or modifies various apoptosis pathways, leading to the development of human cancer. Cell death occurs in an active manner that maintains tissue homeostasis and eliminates potentially harmful cells through regulated cell death processes, including apoptosis, autophagic cell death, and necroptosis. In this review, we discuss the involvement of miRNAs in regulating cell death pathways in cancers and the potential therapeutic functions of miRNAs in cancer treatment.

Phytochemicals are chemical compounds that exist in plants and serve various functions such as protecting against pests, UV radiation, and diseases

WP1130, a partially selective deubiquitinases (DUB) inhibitor, inhibits the deubiquitinating activities of USP5, USP9X, USP14, USP37, and UCHL1. In this study, we investigate whether WP1130 exerts sensitizing effect on TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. Combinations of WP1130 and TRAIL significantly induced apoptosis in renal carcinoma, lung carcinoma and hepatocellular carcinoma cells, but not in normal cells (human mesangial cells (MC) and normal mouse kidney cells (TCMK-1)). The downregulation of c-FLIP protein expression was involved in combined treatment-induced apoptosis. WP1130-induced c-FLIP downregulation was regulated by microRNA (miR)-708 upregulation via inhibition of USP9X. Interestingly, knockdown of USP9X markedly induced c-FLIP downregulation, upregulation of miR-708 expression and sensitivity to TRAIL. Furthermore, ectopic expression of USP9X prevented c-FLIP downregulation and apoptosis upon combined treatment. In sum, WP1130 sensitized TRAIL-induced apoptosis through miR-708-mediated downregulation of c-FLIP by inhibition of USP9X.

Kyong-Jin Jung, Kun Woo Lee, Chul Hyun Park, Tae-Jin Lee, Joo-Young Kim, Eon-Gi Sung, Seong Yong Kim, Byung Ik Jang, and In-Hwan Song. Gut and Liver 1999;0:. https://doi.org/10.5009/gnl18438

Methylglyoxal (MGO) is a reactive dicarbonyl metabolite of glucose, and its plasma levels are elevated in patients with diabetes. Studies have shown that MGO combines with the amino and sulphhydryl groups of proteins to form stable advanced glycation end products (AGEs), which are associated with vascular endothelial cell (EC) injury and may contribute to the progression of atherosclerosis. In this study, MGO induced apoptosis in a dose‐dependent manner in HUVECs, which was attenuated by pre‐treatment with z‐VAD, a pan caspase inhibitor. Treatment with MGO increased ROS levels, followed by dose‐dependent down‐regulation of c‐FLIP_L. In addition, pre‐treatment with the ROS scavenger NAC prevented the MGO‐induced down‐regulation of p65 and c‐FLIP_L, and the forced expression of c‐FLIP_L attenuated MGO‐mediated apoptosis. Furthermore, MGO‐induced apoptotic cell death in endothelium isolated from mouse aortas. Finally, MGO was found to induce apoptosis by down‐regulating p65 expression at both the transcriptional and posttranslational levels, and thus, to inhibit c‐FLIP_L mRNA expression by suppressing NF‐κB transcriptional activity. Collectively, this study showed that MGO‐induced apoptosis is dependent on c‐FLIP_L down‐regulation via ROS‐mediated down‐regulation of p65 expression in endothelial cells.