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E3 ligases are a class of enzymes that can transfer ubiquitin to substrates for their degradation, which are of importance in cellular homeostasis. Since many oncogenic or tumor-suppressive proteins are reported to be regulated by the ubiquitin-proteasome system (UPS), E3 ligases, which function as substrate interacting modules, have been attracting more and more attention as promising anticancer drug targets due to their pivotal role in conferring substrate specificity. Generally, based on their molecular structure and functional mechanism, E3 ligases can be divided into three major types: homologous to E6-associated protein C-terminus (HECT), really interesting new gene (RING), and RING-in-between-RING (RBR) E3 ligases. Based on the significance of their functions, more bioactive compounds targeting E3 ligases should be developed in the future. In this review, we discuss the important roles of E3 ligases involved in cancer as well as available bioactive compounds targeting various E3 ligases for potential anticancer activity. [ABSTRACT FROM AUTHOR]

Oleanolic acid (OA) is a natural triterpenoid that is widely distributed in edible and medicinal plants. OA exerts anti-tumor activity on a wide range of cancer cells primarily through inducing apoptosis. Dysregulated ERK signaling is closely complicated in the biology of cancer, such as metastasis, proliferation, and survival, and it can be activated by various stimuli. In this study, we found that OA induced the activation of ERK in cancer cells. ERK activation compromised the apoptosis induced by OA. Blocking ERK activation by U0126 or siRNAs was able to potentiate the pro-apoptotic activity of OA on cancer cells. OA was shown to promote ERK-dependent Nrf2 expression in cancer cells, and in turn, Nrf2 expression was able to suppress OA-induced ROS generation. Blockade of Nrf2 expression was able to increase ROS levels and apoptotic death in cancer cells. In conclusion, we provided evidences that ERK activation is a mechanism underlying the resistance of cancer cells to OA-induced apoptosis and targeting ERK is a promising strategy to enhance the anti-tumor efficacy of OA. [ABSTRACT FROM AUTHOR]

Dysregulated MAPK/ERK signaling is implicated in one-third of human tumors and represents an attractive target for the development of anticancer drugs. Similarly, elevated protein O-GlcNAcylation and O-GlcNAc transferase (OGT) are detected in various cancers and serve as attractive novel cancer-specific therapeutic targets. However, the potential connection between them remains unexplored. Here, a positive correlation was found between the activated MAPK/ERK signaling and hyper-O-GlcNAcylation in various cancer types and inhibition of the MAPK/ERK signaling by 10 µM U0126 significantly decreased the expression of OGT and O-GlcNAcylation in H1299, BPH-1 and DU145 cells; then, the pathway analysis of the potential regulators of OGT obtained from the UCSC Genome Browser was done, and ten downstream targets of ERK pathway were uncovered; the following results showed that ELK1, one of the ten targets of ERK pathway, mediated ERK signaling-induced OGT upregulation; finally, the MTT assay and the soft agar assay showed that the inhibition of MAPK/ERK signaling reduced the promotion effect of hyper-O-GlcNAcylation on cancer cell proliferation and anchorage-independent growth. Taken together, our data originally provided evidence for the regulatory mechanism of hyper-O-GlcNAcylation in tumors, which will be helpful for the development of anticancer drugs targeting to hyper-O-GlcNAcylation. This study also provided a new mechanism by which MAPK/ERK signaling-enhanced cancer malignancy. Altogether, the recently discovered oncogenic factor O-GlcNAc was linked to the classical MAPK/ERK signaling which is essential for the maintenance of malignant phenotype of cancers. [ABSTRACT FROM AUTHOR]

Temozolomide (TMZ) is an effective agent for clinical glioma treatment, but the innate and acquired resistance of glioma always limits its application. Although some advances have been achieved to elucidate the molecular mechanism underlying TMZ resistance, the role of Nrf2 (a principle regulator of cellular defense against drugs and oxidative stress) has not been well established in the acquisition of this phenotype. Our data showed that TMZ treatment induces the activation of Nrf2 and p38 MAPK signaling in glioma cells, while p38 inhibition abolished the effect of TMZ on Nrf2. Further study revealed that Nrf2 silencing was able to enhance the response of glioma cells to TMZ. Additionally, Nrf2 overexpression overrides the effect of p38 MAPK activation on Temozolomide resistance. In conclusions, we identified a p38 MAPK/Nrf2 signaling as a key molecular network contributing to TMZ resistance of glioma, and provided evidence that suppressing this signaling may be a promising strategy to improve TMZ's therapeutic efficiency. [ABSTRACT FROM AUTHOR]

It has been demonstrated that numerous microRNAs (miRNAs) have potent tumor-suppressing effects on a variety of cancers, implicating a possible application of miRNA in tumor therapy. Oncolytic adenovirus is a suitable vector to deliver tumor suppressor genes for treatment of cancers. However, it remains unknown whether co-expression of tumor suppressor genes and miRNAs can contribute to a more potent antitumor capacity within an oncolytic adenovirus delivery system. In this study, we found that expression of miRNA-34a was reduced in hepatocellular carcinoma (HCC), and the reduced expression of miRNA-34a was associated with worse outcome of HCC patients. Thus, we developed an oncolytic adenoviral vector, AdCN205, to co-express miRNA-34a and IL-24 driven by an adenovirus endogenous E3 promoter in HCC cells. High levels of miRNA-34a and IL-24 expression were detected in AdCN205-IL-24-miR-34a-infected HCC cells. AdCN205-IL-24-miR-34a significantly induced dramatic antitumor activity, as compared with that induced by AdCN205-IL-24 or AdCN205-miR-34a alone. Transfer of miRNA-34a into HCC cells inhibited the expression of its target genes, Bcl-2 and SIRT1. Treatment of established xenograft HCC tumors with AdCN205-IL-24-miR-34a in a mouse model resulted in complete tumor regression without recurrence. Taken together, our data provide a promising and reasonable delivery strategy of double-aimed cancer therapy, in which miRNAs and tumor-suppressing genes are used simultaneously. [ABSTRACT FROM AUTHOR]

Cancer stem cell/tumor-initiating cell (CSC/TIC) is a subclass of cancer cells possessing parts of properties of normal stem cell. It has a high capacity of proliferation and plays a pivotal role in tumor recurrence and tumor resistance to radiotherapy and chemotherapy. At present, small molecule inhibitors and fusion proteins are widely used in the CSC-targeting strategy. Gene-virotherapy, which uses oncolytic adenovirus as a vector to mediate the expression of therapeutic gene, shows a significant superiority to other regimens of cancer treatment and has a good efficacy in the treatment of solid tumors. Thus, it is a promising choice to apply gene-virotherapy into the CSC-targeting treatment. Based on the molecular mechanism underlying CSC self-renewal, a series of effective strategies for targeting CSC have been established. This review will summarize the recent research progresses on CSC-targeting treatment. [ABSTRACT FROM AUTHOR]