Zinc cooperates with p53 to inhibit the activity of mitochondrial aconitase through reactive oxygen species accumulation.

Metabolic reprogramming is a central hallmark of cancer. Therefore, targeting metabolism may provide an effective strategy for identifying promising drug targets for cancer treatment. In prostate cancer, cells undergo metabolic transformation from zinc-accumulating, citrate-producing cells to citrate-oxidizing malignant cells with lower zinc levels and higher mitochondrial aconitase (ACO2) activity. ACO2 is a Krebs cycle enzyme that converts citrate to isocitrate and is sensitive to reactive oxygen species (ROS)-mediated damage. In this study, we found that the expression of ACO2 is positively correlated with the malignancy of prostate cancer. Both zinc and p53 can lead to an increase in ROS. ACO2 can be a target for remodeling metabolism by sensing changes in the ROS levels of prostate cancer. Our results indicate that targeting ACO2 through zinc and p53 can change prostate cancer metabolism, and thus provides a potential new therapeutic strategy for prostate cancer.

Zinc promotes prostate cancer cell chemosensitivity to paclitaxel by inhibiting epithelial-mesenchymal transition and inducing apoptosis.

BACKGROUND: Paclitaxel (PTX) is a first-line chemotherapeutic drug for the treatment of prostate cancer. However, most patients develop resistance and metastasis, and thus new therapeutic approaches are urgently required. Recent studies have identified widespread anti-tumor effects of zinc (Zn) in various tumor cell lines, especially prostate cancer cells. In this study, we examined the effects of Zn as an adjuvant to PTX in prostate cancer cells. METHODS: PC3 and DU145 cells were treated with different concentrations of Zn and/or PTX. MTT assay was used to detect cell viability. Real-time cell analysis (RTCA) and microscopy were used to observe morphological changes in cells. Western blotting was used to detect the expression of epithelial-mesenchymal transition (EMT)-related proteins. qPCR (reverse transcription-polymerase chain reaction) was used to examine changes in TWIST1 mRNA levels. Cell invasion and migration were detected by scratch and transwell assays. shRNA against TWIST1 was used to knockdown TWIST1. Colony formation assay was used to detect cell proliferation, while Annexin V and propidium iodide (PI) staining was used to detect cell apoptosis. RESULTS: Zn and PTX increased proliferation inhibition in a dose- and time-dependent manner in prostate cancer cells, while Zn increased prostate cancer cell chemosensitivity to PTX. Combined Zn and PTX inhibited prostate cancer cell invasion and migration by downregulating the expression of TWIST1. Furthermore, knockdown of TWIST1 increased the sensitivity of prostate cancer cells to PTX. In addition, Zn and PTX reduced cell proliferation and induced apoptosis in prostate cancer cells. CONCLUSIONS: Our results demonstrated that Zn and PTX combined therapy inhibits EMT by reducing the expression of TWIST1, which reduces the invasion and migration of prostate cancer cells. SiTWIST1 increased the sensitivity of prostate cancer cells to PTX. In addition, with prolonged treatment, Zn and PTX inhibited proliferation and led to prostate cancer cell apoptosis. Therefore, Zn may be a potential adjuvant of PTX in treating prostate cancer and combined treatment may offer a promising therapeutic strategy for prostate cancer.

Zinc and p53 disrupt mitochondrial binding of HK2 by phosphorylating VDAC1.

Many cell death regulators physically or functionally interact with metabolic enzymes. These interactions provide insights into mechanisms of anticancer treatments from the perspective of tumor cell metabolism and apoptosis. Recent studies have shown that zinc and p53 not only induce tumor cell apoptosis, but also regulate tumor cell metabolism. However, the underlying mechanism is complex and remains unclear, making further research imperative to provide clues for future cancer treatments. In this study, we found that hexokinase 2 (HK2), which has dual metabolic and apoptotic functions, is downstream of zinc and p53 in both prostate cancer patient tissue and prostate cancer cell lines. Notably, the mitochondrial location of HK2 is crucial for its function. We demonstrate that zinc and p53 disrupt mitochondrial binding of HK2 in prostate cancer cells by phosphorylating VDAC1, which is mediated by protein kinase B (Akt) inhibition and glycogen synthase kinase 3ß (GSK3ß) activation. In addition, we found that zinc combined with p53 significantly inhibited tumor growth in a prostate cancer cell xenograft model. Therefore, interference of the mitochondrial localization of HK2 by zinc and p53 may provide a new treatment approach for cancer.

Circular RNA GRB10 as a competitive endogenous RNA regulating nucleus pulposus cells death in degenerative intervertebral disk.

Intervertebral disc degeneration (IDD) is an important factor leading to low back pain, but the underlying mechanisms remain poorly understood. Compared with normal nucleus pulposus (NP) tissues, the expression of circ-GRB10 was downregulated in IDD. Furthermore, overexpression of circ-GRB10 inhibited NP cell apoptosis. circ-GRB10 could sequester miR-328-5p, which could potentially lead to the upregulation of target genes related to cell proliferation via the ErbB pathway. In conclusion, the present study revealed that circ-GRB10/miR-328-5p/ERBB2 signaling pathway is involved in IDD development, suggesting that circ-GRB10 might be a novel therapeutic target for IDD.

Silencing Transmembrane Protein 45B (TNEM45B) Inhibits Proliferation, Invasion, and Tumorigenesis in Osteosarcoma Cells.

Transmembrane protein 45B (TMEM45B) is a member of the TMEM family of proteins and has been reported to be expressed abnormally in different kinds of human tumors. However, the biological function of TMEM45B in osteosarcoma remains unclear. The objective of this study was to investigate the role of TMEM45B in regulating the biological behavior of osteosarcoma cells. Our results demonstrated that the expression of TMEM45B at both the protein and mRNA levels was dramatically upregulated in human osteosarcoma cell lines. Knockdown of TMEM45B significantly suppressed the proliferation, migration, and invasion of U2OS cells in vitro. Mechanistically, knockdown of TMEM45B sharply downregulated the expression level of ß-catenin, cyclin D1, and c-Myc in U2OS cells. Finally, knockdown of TMEM45B attenuated tumor growth in transplanted U2OS-derived tumors in nude mice. Taken together, our results demonstrated that TMEM45B plays an important role in regulating the proliferation, migration, and invasion of osteosarcoma cells and that its effects on proliferation and invasion were mediated partially through the Wnt/ß-catenin signaling pathway. These observations support our belief that TMEM45B may serve as an oncogene in the development and progression of osteosarcoma.

Case of Langerhans Cell Histiocytosis That Mimics Meningioma in CT and MRI.

Langerhans cell histiocytosis (LCH) is a rare disorder histologically characterized by the proliferation of Langerhans cells. Here we present the case of a 13-year-old girl with LCH wherein CT and MRI results led us to an initially incorrect diagnosis of meningioma. The diagnosis was corrected to LCH based on pathology findings. An intracranial mass was found mainly in the dura mater, with thickening of the surrounding dura. It appeared to be growing downward from the calvaria, pressing on underlying brain tissue, and had infiltrated the inner skull, causing a bone defect. The lesion was calcified with the typical dural tail sign. The dural origin of the lesion was verified upon surgical dissection. There are no previous reports in the literature describing LCH of dural origin presenting in young patients with typical dural tail signs and meningioma-like imaging findings. The current case report underscores the need for thorough histological and immunocytochemical examinations in LCH differential diagnosis.

[Changes of osteocalcin in bone and bone marrow in tail suspended rats].

OBJECTIVE: To study osteocalcin [correction of osteocakin] (OC) changes in bone and marrow and calcium deposition in bone and cartilage under simulated weightlessness. METHOD: Twenty SD rats were randomly divided into 14 d and 28 d tail suspension group and 2 corresponding control groups. Histological samples were in situ hybridized and trichrome stained. RESULT: OC expression of bone and marrow of rats were lower in tail suspended rats than that in the control (P<0.05). OC expression in 14 d tail suspended rats were higher than that in 28 d tail suspended group (P<0.05). Mineralization was inhibited, and demineralization of femur [correction of furmer] and cartilage mineralized matrix was prominent. Demineralization was more prominent in 28 d group. CONCLUSION: OC levels in bone and marrow of rats were lower after tail suspension. Calcium deposition was inhibited in bone and cartilage. Demineralization was prominent after long term hindlimb unloading.