Immunosuppressive tumor microenvironment (TME) and ascites-derived spheroids in ovarian cancer (OC) facilitate tumor growth and progression, and also pose major obstacles for cancer therapy. The molecular pathways involved in the OC-TME interactions, how the crosstalk impinges on OC aggression and chemoresistance are not well-characterized. Here, we demonstrate that tumor-derived UBR5, an E3 ligase overexpressed in human OC associated with poor prognosis, is essential for OC progression principally by promoting tumor-associated macrophage recruitment and activation via key chemokines and cytokines. UBR5 is also required to sustain cell-intrinsic β-catenin-mediated signaling to promote cellular adhesion/colonization and organoid formation by controlling the p53 protein level. OC-specific targeting of UBR5 strongly augments the survival benefit of conventional chemotherapy and immunotherapies. This work provides mechanistic insights into the novel oncogene-like functions of UBR5 in regulating the OC-TME crosstalk and suggests that UBR5 is a potential therapeutic target in OC treatment for modulating the TME and cancer stemness.

Acute lymphoblastic leukaemia (ALL) is the most prevalent childhood malignancy. Although most children with ALL are cured, there is still a group of patients for which therapy fails owing to severe toxicities and drug resistance. Ginsenoside Rh2 (GRh2), a major bioactive component isolated from Panax ginseng, has been shown to have a therapeutic effect on some tumors. However, the molecular mechanisms of cell death induced by 20(S)-GRh2 in ALL cells remains unclear. In this study, we showed that 20(S)-GRh2 inhibited the cell growth and induced mitochondria-dependent apoptosis and autophagy. But it has no cytotoxic effect on human normal blood cells. Furthermore, autophagy plays a protective role in 20(S)-GRh2-induced apoptosis in ALL cell lines and human primary ALL cells. We demonstrated that either genetic or pharmacologic inhibition of autophagy could be more effective in reducing viability and enhancing 20(S)-GRh2-induced toxicity than 20(S)-GRh2 treatment alone. In addition, inhibition of autophagy could aggravate mitochondrial ROS generation and mitochondrial damage, and then accelerate mitochondria-dependent apoptosis. Taken together, these results suggest that inhibition of autophagy can sensitize ALL cells towards 20(S)-GRh2. The appropriate inhibition of autophagy could provide a powerful strategy to increase the potency of 20(S)-GRh2 as a novel anticancer agent for ALL therapy.

Cyclodextrins (CDs) can improve the productivity of steroid biotransformation by enhancing substrate solubility. CDs can be recycled by grafting them with appropriate carriers. Loofah fiber is an excellent grafting material for CDs, and can be applied to the biotransformation and recycling of β-cyclodextrin (β-CD). In this work, a technique for recycling β-CD in cortisone acetate (CA) biotransformation by Arthrobacter simplex CPCC 140451 was studied. Loofah fiber-grafted β-CD (LF-β-CD) was prepared using epichlorohydrin, which is a cross-linking agent. The grafting yield of β-CD was 74.8 mg g dried fibers. LF-β-CD could increase the solubility of CA and enhance biotransformation. The initial conversion rate of CA was 1.5-fold higher than that of the blank group. LF-β-CD was also used in biocatalytic reactions for eight cycles, and it maintained the conversion ratio of CA at approximately 90%. Given the above positive results, LF-β-CD can be utilized in biotechnological recycling applications. This method can also be applied to CD derivatives and hydrophobic compounds.

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The human UBR5 (also known as EDD) is a single polypeptide chain HECT-type E3 ubiquitin ligase essential for embryonic development in mammals. Although widely expressed, UBR5 is markedly amplified and overexpressed in breast, ovarian, prostate, gastric and pancreatic cancers. Dysregulated UBR5 functions like an oncoprotein to promote cancer growth and metastasis, making UBR5 a potential target for therapeutics. Unexpectedly, we found that human UBR5 assembles a dimer and a tetramer in solution. We determined the dimer structure at 2.8 Å and the tetramer structure at 3.5 Å average resolution. UBR5 is a crescent shaped molecule with a seven-bladed β-propeller and two small β-barrel domains (SBB1/2) at the N-terminal region, a catalytic HECT domain at the C-terminus, and an extended helical scaffold and an N-degron-recognizing UBR box in the middle. The dimer is assembled as a stable head-to-tail dimer via extensive interactions in the middle helical scaffold region. The tetramer is assembled via SBB2-SBB2 interaction from two face-to-face dimers, forming a large cage with all four catalytic HECT domains facing the central cavity. Importantly, the N-terminal region of one subunit and the HECT of the other form an intermolecular jaw in the dimer. Using enzymatic and cellular assays, we showed that the jaw-lining residues are important for function, suggesting that the intermolar jaw functions to recruit ubiquitin loaded E2 to UBR5 for the transthiolation reaction. Further work is needed to understand how oligomerization regulates the UBR5 ligase activity. This work provides a framework for structure-based anticancer drug development against the distinctive HECT E3 ligase and contributes to a growing appreciation of E3 ligase diversity.

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Breast cancer (BC) is one of the most diagnosed cancers worldwide and is the second cause of cancer related death in women. The most frequent cause of BC-related deaths, like many cancers, is metastasis. However, metastasis is a complicated and poorly understood process for which there is a shortage of accurate prognostic indicators and effective treatments. With the rapid and ever-evolving development and application of genomic sequencing technologies, many novel molecules were identified that play previously unappreciated and important roles in the various stages of metastasis. In this review, we summarize current advancements in the functional genomic analysis of BC metastasis and discuss about the potential prognostic and therapeutic implications from the recent genomic findings.

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