High-fat diet promotes prostate cancer metastasis via RPS27.

BACKGROUND: Metastasis is the leading cause of death among prostate cancer (PCa) patients. Obesity is associated with both PCa-specific and all-cause mortality. High-fat diet (HFD) is a risk factor contributing to obesity. However, the association of HFD with PCa metastasis and its underlying mechanisms are unclear. METHODS: Tumor xenografts were conducted by intrasplenic injections. The ability of migration or invasion was detected by transwell assay. The expression levels of RPS27 were detected by QRT-PCR and western blot. RESULTS: The present study verified the increase in PCa metastasis caused by HFD in mice. Bioinformatics analysis demonstrated increased RPS27 in the experimentally induced PCa in HFD mice, indicating that it is an unfavorable prognostic factor. Intrasplenic injections were used to demonstrate that RPS27 overexpression promotes, while RPS27 knockdown significantly reduces, PCa liver metastasis. Moreover, RPS27 inhibition suppresses the effects of HFD on PCa metastasis. Further mRNA sequencing analysis revealed that RPS27 promotes PCa metastasis by selectively enhancing the expression of various genes. CONCLUSION: Our findings indicate that HFD increases the risk of PCa metastasis by elevating RPS27 expression and, subsequently, the expression of genes involved in PRAD progression. Therefore, RPS27 may serve as a novel target for the diagnosis and treatment of metastatic PCa.

Prostate cancer cells synergistically defend against CD8+ T cells by secreting exosomal PD-L1.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains fatal and incurable, despite a variety of treatments that can delay disease progression and prolong life. Immune checkpoint therapy is a promising treatment. However, emerging evidence suggests that exosomal programmed necrosis ligand 1 (PD-L1) directly binds to PD-1 on the surface of T cells in the drain lineage lymph nodes or neutralizes administered PD-L1 antibodies, resulting in poor response to anti-PD-L1 therapy in mCRPC. MATERIALS AND METHODS: Western blotting and immunofluorescence were performed to compare PD-L1 levels in exosomes derived from different prostate cancer cells. PC3 cells were subcutaneously injected into nude mice, and then ELISA assay was used to detect human specific PD-L1 in exosomes purified from mouse serum. The function of CD8+ T cells was detected by T cell mediated tumor cell killing assay and FACS analysis. A subcutaneous xenograft model was established using mouse prostate cancer cell RM1, exosomes with or without PD-L1 were injected every 3 days, and then tumor size and weight were analyzed to evaluate the effect of exosomal PD-L1. RESULTS: Herein, we found that exosomal-PD-L1 was taken up by tumor cells expressing low levels of PD-L1, thereby protecting them from T-cell killing. Higher levels of PD-L1 were detected in exosomes derived from the highly malignant prostate cancer PC3 and DU145 cell lines. Moreover, exosomal PD-L1 was taken up by the PD-L1-low-expressing LNCaP cell line and inhibited the killing function of CD8-T cells on tumor cells. The growth rate of RM1-derived subcutaneous tumors was decreased after knockdown of PD-L1 in tumor cells, whereas the growth rate recovered following exosomal PD-L1 tail vein injection. Furthermore, in the serum of mice with PCa subcutaneous tumors, PD-L1 was mainly present on exosomes. CONCLUSION: In summary, tumor cells share PD-L1 synergistically against T cells through exosomes. Inhibition of exosome secretion or prevention of PD-L1 sorting into exosomes may improve the therapeutic response of prostate tumors to anti-PD-L1 therapy.

Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression.

DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence, and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted DBC1 to interact with SIAH2 but not OTUD5, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin-proteasome pathway. SIAH2 knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout of SIAH2/CCAR2. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.

Pt nanoenzyme decorated yolk-shell nanoplatform as an oxygen generator for enhanced multi-modality imaging-guided phototherapy.

The unsatisfactory efficacy of conventional theranostic agents in ablating tumor poses urgent demands on the development of high-performance integrated theranostic agents utilizing rising nanotechnology. To cope with the existing limitations, here we presented an intelligent nanoplatform based on yolk-shell Fe3O4@polydopamine prepared by mussel-inspired polydopamine chemistry and sacrificial template method as well as subsequent incorporation of Pt nanoparticles and chlorine 6 (Ce6) by in situ reduction and electrostatic adsorption for photodynamic therapy (PDT) and photothermal (PTT). The resultant nanoplatform could effectively deliver photosensitizer Ce6 to tumor sites, then promoting the decomposition of endogenous H2O2 to oxygen, finally achieving enhanced PDT therapy, which is demonstrated by in vitro and in vivo evaluations. Importantly, the generated oxygen bubbles could improve the echogenicity signal of yolk-shell microspheres and thereby provide enhanced ultrasonic (US) signal for imaging solid tumors. Overall, the synergistic combination of magnetic Fe3O4, green polydopamine, catalytic Pt nanoparticles, photosensitive Ce6 enabled the hybrid nanoplatform to have good biocompatibility, efficient tumor accumulation, excellent phototherapy efficiency, high T2-weighted magnetic resonance imaging (MRI) and fluorescence imaging ability (FL). Our study integrating the merits of PDT/PTT and US/MRI/FL into a single nanoplatform will open an avenue of therapeutic strategy toward biomedical applications.

Receptor-mediated mitophagy regulates EPO production and protects against renal anemia.

Erythropoietin (EPO) drives erythropoiesis and is secreted mainly by the kidney upon hypoxic or anemic stress. The paucity of EPO production in renal EPO-producing cells (REPs) causes renal anemia, one of the most common complications of chronic nephropathies. Although mitochondrial dysfunction is commonly observed in several renal and hematopoietic disorders, the mechanism by which mitochondrial quality control impacts renal anemia remains elusive. In this study, we showed that FUNDC1, a mitophagy receptor, plays a critical role in EPO-driven erythropoiesis induced by stresses. Mechanistically, EPO production is impaired in REPs in Fundc1-/- mice upon stresses, and the impairment is caused by the accumulation of damaged mitochondria, which consequently leads to the elevation of the reactive oxygen species (ROS) level and triggers inflammatory responses by up-regulating proinflammatory cytokines. These inflammatory factors promote the myofibroblastic transformation of REPs, resulting in the reduction of EPO production. We therefore provide a link between aberrant mitophagy and deficient EPO generation in renal anemia. Our results also suggest that the mitochondrial quality control safeguards REPs under stresses, which may serve as a potential therapeutic strategy for the treatment of renal anemia.

Versatile Nanoplatforms with enhanced Photodynamic Therapy: Designs and Applications.

As an emerging antitumor strategy, photodynamic therapy (PDT) has attracted intensive attention for the treatment of various malignant tumors owing to its noninvasive nature and high spatial selectivity in recent years. However, the therapeutic effect is unsatisfactory on some occasions due to the presence of some unfavorable factors including nonspecific accumulation of PS towards malignant tissues, the lack of endogenous oxygen in tumors, as well as the limited light penetration depth, further hampering practical application. To circumvent these limitations and improve real utilization efficiency, various enhanced strategies have been developed and explored during the past years. In this review, we give an overview of the state-of-the-art advances progress on versatile nanoplatforms for enhanced PDT considering the enhancement from targeting or responsive, chemical and physical effect. Specifically, these effects mainly include organelle-targeting function, tumor microenvironment responsive release photosensitizers (PS), self-sufficient O2 (affinity oxygen and generating oxygen), photocatalytic water splitting, X-rays light stimulate, surface plasmon resonance enhancement, and the improvement by resonance energy transfer. When utilizing these strategies to improve the therapeutic effect, the advantages and limitations are addressed. Finally, the challenges and prospective will be discussed and demonstrated for the future development of advanced PDT with enhanced efficacy.

The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression.

The interactions between tumor cells with their microenvironments, including hypoxia, acidosis and immune cells, lead to the tumor heterogeneity which promotes tumor progression. Here, we show that SIAH2-NRF1 axis remodels tumor microenvironment through regulating tumor mitochondrial function, tumor-associated macrophages (TAMs) polarization and cell death for tumor maintenance and progression. Mechanistically, low mitochondrial gene expression in breast cancers is associated with a poor clinical outcome. The hypoxia-activated E3 ligase SIAH2 spatially downregulates nuclear-encoded mitochondrial gene expression including pyruvate dehydrogenase beta via degrading NRF1 (Nuclear Respiratory Factor 1) through ubiquitination on lysine 230, resulting in enhanced Warburg effect, metabolic reprogramming and pro-tumor immune response. Dampening NRF1 degradation under hypoxia not only impairs the polarization of TAMs, but also promotes tumor cells to become more susceptible to apoptosis in a FADD-dependent fashion, resulting in secondary necrosis due to the impairment of efferocytosis. These data represent that inhibition of NRF1 degradation is a potential therapeutic strategy against cancer.

Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-ß signalling pathways.

The evolutionarily conserved Hippo pathway is a regulator that controls organ size, cell growth and tissue homeostasis. Upstream signals of the Hippo pathway have been widely studied, but how microenvironmental factors coordinately regulate this pathway remains unclear. In this study, we identify LIM domain protein Zyxin, as a scaffold protein, that in response to hypoxia and TGF-ß stimuli, forms a ternary complex with Lats2 and Siah2 and stabilizes their interaction. This interaction facilitates Lats2 ubiquitination and degradation, Yap dephosphorylation and subsequently activation. We show that Zyxin is required for TGF-ß and hypoxia-induced Lats2 downregulation and deactivation of Hippo signalling in MDA-MB-231 cells. Depletion of Zyxin impairs the capability of cell migration, proliferation and tumourigenesis in a xenograft model. Zyxin is upregulated in human breast cancer and positively correlates with histological stages and metastasis. Our study demonstrates that Zyxin-Lats2-Siah2 axis may serve as a potential therapeutic target in cancer treatment.

Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase.

The Hippo signalling pathway plays important roles in animal development, physiology and tumorigenesis. Understanding how the activity of this pathway is regulated by the cellular microenvironment remains a major challenge. Here we elucidate a molecular mechanism by which hypoxia deactivates Hippo signalling. We demonstrate that the E3 ubiquitin ligase SIAH2 stimulates YAP by destabilizing LATS2, a critical component of the Hippo pathway, in response to hypoxia. Loss of SIAH2 suppresses tumorigenesis in a LATS2-dependent manner in a xenograft mouse model. We further show that YAP complexes with HIF1α and is essential for HIF1α stability and function in tumours in vivo. LATS2 is downregulated in human breast tumours and negatively correlates with SIAH2 expression levels, indicating that the SIAH2-LATS2 pathway may have a role in human cancer. Our data uncover oxygen availability as a microenvironment signal for the Hippo pathway and have implications for understanding the regulation of Hippo signalling in tumorigenesis.

A diterpenoid derivate compound targets selenocysteine of thioredoxin reductases and induces Bax/Bak-independent apoptosis.

We have previously shown that the natural diterpenoid derivative S3 induced Bim upregulation and apoptosis in a Bax/Bak-independent manner. However, the exact molecular target(s) of S3 and the mechanism controlling Bim upregulation are still not clear. Here, we identify that S3 targets the selenoproteins TrxR1 and TrxR2 at the selenocysteine residue of the reactive center of the enzymes and inhibits their antioxidant activities. Consequently, cellular ROS is elevated, leading to the activation of FOXO3a, which contributes to Bim upregulation in Bax/Bak-deficient cells. Moreover, S3 retards tumor growth in subcutaneous xenograft tumors by inhibiting TrxR activity in vivo. Our studies delineate the signaling pathway controlling Bim upregulation, which results in Bax/Bak-independent apoptosis and provide evidence that the compounds can act as anticancer agents based on mammalian TrxRs inhibition.