Tumorigenesis, tumor growth, and prognosis are highly related to gene alterations and post-translational modifications (PTMs). Ubiquitination is a critical PTM that governs practically all aspects of cellular function. An increasing number of studies show that E3 ubiquitin ligases (E3s) are important enzymes in the process of ubiquitination that primarily determine substrate specificity and thus need to be tightly controlled. Among E3s, neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) has been shown to play a critical role in modulating the proliferation, migration, and invasion of cancer cells and the sensitivity of cancer cells to anticancer therapies via regulating multiple substrates. This review discusses some significant discoveries on NEDD4-1 substrates and the signaling pathways in which NEDD4-1 participates. In addition, we introduce the latest potential therapeutic strategies that inhibit or activate NEDD4-1 activity using small molecules. NEDD4-1 likely acts as a novel drug target or diagnostic marker in the battle against cancer.

Dihydroartemisinin (DHA), an active metabolite and derivative of artemisinin, is the most effective antimalarial drug and has strong antitumor activity in various tumor types. It has recently been reported that DHA can induce autophagy and has significant effects on multiple myeloma (MM), but the mechanisms and the relationship between the autophagy and apoptosis induced by DHA remain to be elucidated. Herein, we demonstrated that DHA significantly induces cell death in a dose- and time-dependent manner via the extrinsic and intrinsic apoptosis pathways. Moreover, DHA-induced autophagy, which plays a prodeath role in MM, can regulate canonical apoptosis and vice versa. Furthermore, the P38/MAPK signaling pathway is responsible for decreased autophagy and increased apoptosis. DHA induces autophagy and apoptosis also through the inhibition of the Wnt/β-catenin signaling pathway. In addition, DHA shows a strong effect in a xenograft mouse model. Collectively, these findings reveal that DHA, as an artemisinin-based drug, could be an effective and safe therapeutic agent for MM.

Background: Protopine is an isoquinoline alkaloid that possesses various biological activities including the anti-tumour activity. However, the effects of protopine on liver carcinoma cells are still elusive. The aim of this study is to examine the effects of protopine on liver carcinoma cells both in vitro and in vivo. Methods: MTT assay was performed to measure the cell viability. Wound healing and transwell assays were conducted to assess the motility of cells. Cellular apoptosis and ROS levels were measured by the flow cytometry. Western blotting assay was used to measure the change of proteins. The cytotoxicity of protopine was also evaluated in xenograft mice. Results: Protopine inhibited viabilities and triggered apoptosis via the intrinsic pathway in a caspase-dependent manner in liver carcinoma cells. Furthermore, protopine also induced accumulation of intracellular ROS which further led to the inhibition of PI3K/Akt signalling pathway. Finally, in vivo study showed that protopine also repressed tumour growth in xenograft mice without noticeable toxicity. Conclusions: Protopine might be used as a potential therapeutic agent for the treatment of liver carcinoma.

With the development of novel therapeutic agents, the survival of multiple myeloma (MM) patients has much improved. However, the disease is incurable due to drug resistance. Previous studies have found that high-mobility group box 1 (HMGB1) is involved in inflammation, angiogenesis, DNA damage repair, and cancer invasion, progression, metastasis and drug resistance and that high HMGB1 expression is associated with poor MM prognosis, yet the role and mechanism of HMGB1 in MM remains unclear. Through gene expression and Oncomine database analyses, we found that HMGB1 is associated with a poor prognosis in MM patients. RNA interference together with gene array analysis, cell proliferation and apoptosis assays, autophagy detection assays, western blotting, and in vivo xenograft models were employed to evaluate the effect of HMGB1 and the mechanism involved in MM drug resistance. MM cell lines and primary MM samples were found to express high levels of HMGB1, which was negatively associated with the 3-year survival of MM patients. HMGB1 knockdown in MM cells enhanced the inhibitory effect of chemotherapy with dexamethasone (Dex) via apoptosis induction. Furthermore, downregulation of HMGB1 activated the mTOR pathway, inhibited autophagy and increased DNA damage induced by Dex by modulating expression of related genes. In vivo, xenograft models showed that after Dex treatment, the tumor burden of HMGB1-knockdown mice was decreased compared with that of control mice. Our research shows that HMGB1 participates in autophagy and DNA damage repair and that downregulation of HMGB1 enhances the sensitivity of MM cells to Dex, suggesting that HMGB1 may serve as a target for MM treatment.

Interleukin-32 promotes the proliferation of multiple myeloma cells by inducing production of IL-6 in bone marrow stromal cells Interleukin-32α promotes the proliferation of multiple myeloma cells by inducing production of IL-6 in bone marrow stromal cells

Multiple myeloma (MM) remains an incurable plasma cell cancer characterized by abnormal secretion of monoclonal immunoglobulins. The molecular mechanism that regulates the drug sensitivity of MM cells is being intensively studied. Here, we report an unexpected finding that the protein encoded by neural precursor cell-expressed developmentally downregulated gene 4L (NEDD4L), which is a HECT E3 ligase, binds the 19S proteasome, limiting its proteolytic function and enhancing autophagy. Suppression of NEDD4L expression reduced bortezomib (Bor) sensitivity in vitro and in vivo, mainly through autophagy inhibition mediated by low NEDD4L expression, which was rescued by an autophagy activator. Clinically, elevated expression of NEDD4L is associated with a considerably increased probability of responding to Bor, a prolonged response duration, and improved overall prognosis, supporting both the use of NEDD4L as a biomarker to identify patients most likely to benefit from Bor and the regulation of NEDD4L as a new approach in myeloma therapy.