Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. The binding of hexokinase 2 to the outer membrane of mitochondria is ...critical for its oncogenic activity. However, the regulation of hexokinase 2 binding to mitochondria remains unclear. Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492. SUMO-specific protease SENP1 mediates the de-SUMOylation of hexokinase 2. SUMO-defective hexokinase 2 preferably binds to mitochondria and enhances both glucose consumption and lactate production and decreases mitochondrial respiration in parallel. This metabolic reprogramming supports prostate cancer cell proliferation and protects cells from chemotherapy-induced cell apoptosis. Moreover, we demonstrate an inverse relationship between SENP1-hexokinase 2 axis and chemotherapy response in prostate cancer samples. Our data provide evidence for a previously uncovered posttranslational modification of hexokinase 2 in cancer cells, suggesting a potentially actionable strategy for preventing chemotherapy resistance in prostate cancer.
Positron emission tomography/computed tomography (PET/CT) is widely used in prostate cancer to evaluate the localized tumor burden and detect symptomatic metastatic lesions early.
18
F-FDG is the ...most used tracer for oncologic imaging, but it has limitations in detecting early-stage prostate cancer.
68
Ga-PSMA is a new tracer that has high specificity and sensibility in detecting local and metastatic tumors. But with the progression of prostate cancer, the enhancement of glucose metabolism in progressive prostate cancer provides a chance for
18
F-FDG. This review focuses on PET/CT in the detection and prognosis of prostate cancer, summarizing the literature on
18
F-FDG and
68
Ga-PSMA in prostate cancer and highlighting that
18
F-FDG has advantages in detecting local recurrence, visceral and lymph node metastases compared to
68
Ga-PSMA in partial progressive prostate cancer and castration-resistant prostate cancer patients. We emphasize
18
F-FDG PET/CT can compensate for the weakness of
68
Ga-PSMA PET/CT in progressive prostate cancer.
The viewpoints of previous studies on the correlation between exercise and cellular lipid peroxidation are contradictory from many perspectives and lack evidence for elder individuals. A new ...systematic review with network meta-analysis is necessary and will have significant practical value to provide high-quality evidence in the development of exercise protocols and an evidence-based guide for antioxidant supplementation for the elderly.
To identify the cellular lipid peroxidation induced by different types of exercise, with or without antioxidant supplementation, in elderly individuals.
Randomized controlled trials that recruited elderly participants and reported cellular lipid peroxidation indicators and were published in peer-reviewed journals in English were searched by a Boolean logic search strategy and screened in the databases PubMed, Medline, Embase, and Web of Science. The outcome measures were the biomarkers of oxidative stress in cell lipids in urine and blood, namely F2-isoprostanes, hydrogen peroxide (LOOH, PEROX, or LIPOX), malondialdehyde (MDA), and thiobarbituric acid reactive substances (TBARS).
7 trials were included. A combination program of aerobic exercise (AE), low-intensity resistance training (LIRT), and a placebo intake (Placebo) and a combination program of aerobic exercise, low-intensity resistance training, and antioxidant supplementation (S) had the most and sub-most potential to dampen cellular lipid peroxidation (AE + LIRT + Placebo: 0.31 in Rank 1 and 0.2 in Rank 2; AE + LIRT + S: 0.19 in Rank 1 and 0.20 in Rank 2); A placebo intake (Placebo) and a blank intervention without exercise (NE) had the most and sub-most potential to induce an enhancement of cellular lipid peroxidation (Placebo: 0.51 in Rank 9 and 0.16 in Rank 8; NE: 0.16 in Rank 9 and 0.28 in Rank 8). All included studies had an unclear risk of selecting reporting. There were no high confidence ratings in all the direct and indirect comparisons, 4 comparisons in the direct evidence structure and 7 comparisons in the indirect evidence structure had moderate confidence.
A combined protocol consisting of aerobic exercise and low-intensity resistance training is recommended to dampen cellular lipid peroxidation. Extra antioxidant supplementation might be unnecessary if an elderly individual has enough aerobic and resistance exercise.
CRD42022367430.
Purpose
Neuroendocrine prostate cancer (NEPC), a highly aggressive subtype of prostate cancer displaying resistance to hormone therapy, presents a poor prognosis and limited therapeutic options. ...Here, we aimed to find novel medication therapies for NEPC and explore the underlying mechanism.
Methods
A high-throughput drug screening utilizing an FDA-approved drug library was performed and ketotifen, an antihistamine agent, was identified as a potential therapeutic candidate for NEPC. The whole-transcriptome sequencing analysis was conducted to explore mechanism of ketotifen inhibitory in NEPC. Multiple cell biology and biochemistry experiments were performed to confirm the inhibitory effect of ketotifen in vitro. A spontaneous NEPC mice model (
PBCre4:Pten
f/f
;
Trp53
f/f
;Rb1
f/f
) was used to reveal the inhibitory effect of ketotifen in vivo.
Results
Our in vitro experiments demonstrated that ketotifen effectively suppressed neuroendocrine differentiation, reduced cell viability, and reversed the lineage switch via targeting the IL-6/STAT3 pathway. Our in vivo results showed that ketotifen significantly prolonged overall survival and reduced the risk of distant metastases in NEPC mice model.
Conclusion
Our findings repurpose ketotifen for antitumor applications and endorse its clinical development for NEPC therapy, offering a novel and promising therapeutic strategy for this formidable cancer subtype.
Abstract
Neuroendocrine prostate cancer is a rapidly progressive and lethal disease characterized by early visceral metastasis, poor prognosis, and limited treatment options. Uncovering the oncogenic ...mechanisms could lead to the discovery of potential therapeutic avenues. Here, we demonstrate that the RNA-binding protein ELAVL3 is specifically upregulated in neuroendocrine prostate cancer and that overexpression of ELAVL3 alone is sufficient to induce the neuroendocrine phenotype in prostate adenocarcinoma. Mechanistically, ELAVL3 is transcriptionally regulated by MYCN and subsequently binds to and stabilizes
MYCN
and
RICTOR
mRNA. Moreover, ELAVL3 is shown to be released in extracellular vesicles and induce neuroendocrine differentiation of adenocarcinoma cells via an intercellular mechanism. Pharmacological inhibition of ELAVL3 with pyrvinium pamoate, an FDA-approved drug, effectively suppresses tumor growth, reduces metastatic risk, and improves survival in neuroendocrine prostate cancer mouse models. Our results identify ELAVL3 as a critical regulator of neuroendocrine differentiation in prostate cancer and propose a drug repurposing strategy for targeted therapies.
The androgen receptor (AR) signaling is a key contributor to tumorigenesis and the progression of prostate cancer. A subset of patients may develop neuroendocrine (NE) features, resulting in ...resistance to androgen deprivation therapy and poor prognosis. In this study, we combined immunostaining and bulk and single-cell transcriptome analyses to better characterize the status of AR in prostate cancer with neuroendocrine differentiation. The exploration of online datasets indicated the existence of AR
HIGH
/NE
HIGH
prostate cancer and revealed that these double-high cases are majorly present in castration-resistant prostate cancer with a less neuroendocrine-transdifferentiated state. We then reviewed 8,194 prostate cancer cases with available immunohistochemistry reports and found 2.3% cases (
n
= 189) that showed at least one of the NE markers (chromogranin A, synaptophysin, and neural cell adhesion molecule 1) being positive in at least 5% of epithelial cells. Within these 189 cases, we observed that 81.0% cases (
n
= 153) showed AR positive and 19.0% (
n
= 36) showed AR negative. Patients with AR loss tumors demonstrated a correlation with adverse clinical stages, indicating a trade-off between AR and advanced disease in neuroendocrine differentiation. Using multiplex immunofluorescence staining, we observed the co-localization of AR and NE markers in prostate cancer cells. In addition, data mining of single-cell transcriptome further confirmed the existence of AR
HIGH
/NE
HIGH
prostate cancer cells in castration-resistant samples and suggested that AR still exerts its androgen response and anti-apoptotic effect in these double-high cells. Thus, our study provides a better understanding of AR signaling in the cellular plasticity of prostate cancer with neuroendocrine differentiation and allows new insights into the therapeutic development.
Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis and resistance to hormone therapy, which has limited therapeutic approaches. Therefore, this ...study aimed to identify a novel treatment for NEPC and provide evidence of its inhibitory effects.
We performed a high-throughput drug screening and identified fluoxetine, originally an FDA-approved antidepressant, as candidate therapeutic agent for NEPC. We carried out both in vitro and in vivo experiments to demonstrate the inhibitory effects of fluoxetine on NEPC models and its mechanism in detail.
Our results demonstrated that fluoxetine effectively curbed the neuroendocrine differentiation and inhibited cell viability by targeting the AKT pathway. Preclinical test in NEPC mice model (PBCre4: Ptenf/f; Trp53f/f; Rb1f/f) showed that fluoxetine effectively prolonged the overall survival and reduced the risk of tumor distant metastases.
This work repurposed fluoxetine for antitumor application, and supported its clinical development for NEPC therapy, which may provide a promising therapeutic strategy.
Thermal magnetic resonance (ThermalMR) accommodates radio frequency (RF)-induced temperature modulation, thermometry, anatomic and functional imaging, and (nano)molecular probing in an integrated RF ...applicator. This study examines the feasibility of ThermalMR for the controlled release of a model therapeutics from thermoresponsive nanogels using a 7.0-tesla whole-body MR scanner en route to local drug-delivery-based anticancer treatments. The capacity of ThermalMR is demonstrated in a model system involving the release of fluorescein-labeled bovine serum albumin (BSA-FITC, a model therapeutic) from nanometer-scale polymeric networks. These networks contain thermoresponsive polymers that bestow environmental responsiveness to physiologically relevant changes in temperature. The release profile obtained for the reference data derived from a water bath setup used for temperature stimulation is in accordance with the release kinetics deduced from the ThermalMR setup. In conclusion, ThermalMR adds a thermal intervention dimension to an MRI device and provides an ideal testbed for the study of the temperature-induced release of drugs, magnetic resonance (MR) probes, and other agents from thermoresponsive carriers. Integrating diagnostic imaging, temperature intervention, and temperature response control, ThermalMR is conceptually appealing for the study of the role of temperature in biology and disease and for the pursuit of personalized therapeutic drug delivery approaches for better patient care.
Inflammatory disorders of the central nervous system such as multiple sclerosis and acute disseminated encephalomyelitis involve an invasion of immune cells that ultimately leads to white matter ...demyelination, neurodegeneration and development of neurological symptoms. A clinical diagnosis is often made when neurodegenerative processes are already ongoing. In an attempt to seek early indicators of disease, we studied the temporal and spatial distribution of brain modifications in experimental autoimmune encephalomyelitis (EAE). In a thorough magnetic resonance imaging study performed with EAE mice, we observed significant enlargement of the ventricles prior to disease clinical manifestation and an increase in free water content within the cerebrospinal fluid as demonstrated by changes in T2 relaxation times. The increase in ventricle size was seen in the lateral, third and fourth ventricles. In some EAE mice the ventricle size started returning to normal values during disease remission. In parallel to this macroscopic phenomenon, we studied the temporal evolution of microscopic lesions commonly observed in the cerebellum also starting prior to disease onset. Our data suggest that changes in ventricle size during the early stages of brain inflammation could be an early indicator of the events preceding neurological disease and warrant further exploration in preclinical and clinical studies.
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