Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc. 

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Neuroscience  

Neuropathic pain is one of the most intractable pain conditions associated with tumor growth compressing and damaging nerves. A troublesome hallmark symptom of neuropathic pain is hypersensitivity to innocuous stimuli, known as "tactile allodynia," which is often refractory to currently available analgesics. Diurnal variations in pain hypersensitivity are common in patients with cancer, but the underlying mechanisms are enigmatic. Herein, we report that spinal expression of lipocalin-2 (LCN2) enhances pain sensitivity of NCTC2472 fibrosarcoma-implanted male mice during specific stages of the diurnal cycle. As the tumor grew, interleukin-6 (IL-6) levels increased in the spinal cord of the mice. Increased IL-6 levels stimulated LCN2 expression in spinal microglia, but this expression was periodically repressed by the circadian clock components REV-ERBα and REV-ERBβ. Notably, intra-spinal dorsal horn injection of lentiviral vectors expressing REV-ERBα or REV-ERBβ in tumor-bearing mice alleviated tactile allodynia. Furthermore, intrathecal injection of SR9009, a synthetic agonist of REV-ERBs, also attenuated cancer-induced pain hypersensitivity, accompanied by suppressing spinal LCN2 expression. These results suggest that temporal elevation of LCN2 expression decreases the threshold of tactile pain hypersensitivity induced by tumor growth. We propose that the circadian clock component of REV-ERBs is an effective target for alleviation of cancer-induced tactile allodynia, identifying a new class of analgesic agents.Significance statement Spinal expression of lipocalin-2 (LCN2) enhances pain sensitivity of NCTC2472 fibrosarcoma-implanted mice during specific stages of the diurnal cycle. Following tumor growth, an increase in interleukin-6 (IL-6) levels within spinal cord induces the microglial expression of LCN2, which is periodically suppressed by the circadian clock components REV-ERBα and REV-ERBβ. The temporal elevation of LCN2 expression decreases the threshold of tactile allodynia induced by tumor growth. Enhanced expression of REV-ERBs in spinal microglial and their pharmacological activation by the synthetic agonist SR9009 alleviate cancer-induced pain hypersensitivity. These findings reveal the circadian machinery affecting cancer-associated intractable pain and propose that REV-ERBs are an effective target for alleviation of cancer-associated neuropathic pain.

DOI： 10.1523/JNEUROSCI.1969-24.2025

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Biological Chemistry  

Malignant cells exhibit a high demand for amino acids to sustain their abnormal proliferation. Particularly, the intracellular accumulation of cysteine is often observed in cancer cells. Previous studies have shown that deprivation of intracellular cysteine in cancer cells results in the accumulation of lipid peroxides in the plasma membrane and induction of ferroptotic cell death, indicating that cysteine plays a critical role in the suppression of ferroptosis. Herein, we found that the oncogenic accumulation of cysteine also contributes to cancer cell proliferation by promoting the cell cycle progression, which is independent of its suppressive effect on ferroptosis. The growth ability of four types of cancer cells, including murine hepatocarcinoma cells, but not of primary hepatocytes, were dependent on the exogenous supply of cysteine. Deprivation of intracellular cysteine in cancer cells induced cell cycle arrest at the G0/G1 phase, accompanied by a decrease in the expression of cyclin D1 and D2 proteins. The cysteine deprivation–induced decrease in D-type cyclin expression was associated with the upregulation of eukaryotic translation initiation factor 4E binding protein 1, which represses the translation of cyclin D1 and D2 proteins by binding to eukaryotic translation initiation factor 4E. Similar results were observed in hepatocarcinoma cells treated with erastin, an inhibitor of cystine/glutamate antiporter, xCT. These findings reveal an unappreciated role of cysteine in regulating the growth of malignant cancer cells and deepen our understanding of the cytotoxic effect of xCT inhibitor to prevent cancer cell proliferation.

DOI： 10.1016/j.jbc.2024.107890

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BACKGROUND: The metabolic reprogramming of amino acids is critical for cancer cell growth and survival. Notably, intracellular accumulation of cysteine is often observed in various cancers, suggesting its potential role in alleviating the oxidative stress associated with rapid proliferation. The liver is the primary organ for cysteine biosynthesis, but much remains unknown about the metabolic alterations of cysteine and their mechanisms in hepatocellular carcinoma cells. METHODS: RNA-seq data from patients with hepatocarcinoma were analyzed using the TNMplot database. The underlying mechanism of the oncogenic alteration of cysteine metabolism was studied in mice implanted with BNL 1ME A.7 R.1 hepatocarcinoma. RESULTS: Database analysis of patients with hepatocellular carcinoma revealed that the expression of enzymes involved in de novo cysteine synthesis was down-regulated accompanying with increased expression of the cystine uptake transporter xCT. Similar alterations in gene expression have also been observed in a syngeneic mouse model of hepatocarcinoma. The enhanced expression of DNA methyltransferase in murine hepatocarcinoma cells caused methylation of the upstream regions of cysteine synthesis genes, thereby repressing their expression. Conversely, suppression of de novo cysteine synthesis in healthy liver cells induced xCT expression by up-regulating the oxidative-stress response factor NRF2, indicating that reduced de novo cysteine synthesis repulsively increases cystine uptake via enhanced xCT expression, leading to intracellular cysteine accumulation. Furthermore, the pharmacological inhibition of xCT activity decreased intracellular cysteine levels and suppressed hepatocarcinoma tumor growth in mice. CONCLUSIONS: Our findings indicate an underlying mechanism of the oncogenic alteration of cysteine metabolism in hepatocarcinoma and highlight the efficacy of alteration of cysteine metabolism as a viable therapeutic target in cancer.

DOI： 10.1186/s40170-024-00352-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Pharmacology and Experimental Therapeutics  

A problem for patients with diabetes is the rise of complications, such as peripheral neuropathy, nephropathy, and retinopathy. Among them, peripheral neuropathy, characterized by numbness and/or hypersensitivity to pain in the extremities, is likely to develop in the early stages of diabetes. Empagliflozin (EMPA), a sodium-glucose cotransporter-2 inhibitor, exerts hypoglycemic effects by preventing glucose reabsorption in proximal tubular cells. EMPA can improve cardiovascular and renal outcomes in diabetic patients, but its suppressive effect on the development of diabetic neuropathy remains unclear. In this study, we demonstrated that optimizing the dosing schedule of EMPA suppressed the development of pain hypersensitivity in streptozotocin (STZ)-induced diabetic model mice maintained under standardized light/dark cycle conditions. A single intraperitoneal administration of STZ to mice induced hyperglycemia accompanied by pain hypersensitivity. Although EMPA did not exert anti-hypersensitivity effect on STZ-induced diabetic mice after the establishment of neuropathic pain, the development of pain hypersensitivity in the diabetic mice was significantly suppressed by daily oral administration of EMPA at the beginning of the dark phase. On the other hand, the suppressive effect was not observed when EMPA was administered at the beginning of the light phase. The hypoglycemic effect of EMPA and its stimulatory effect on urinary glucose excretion were also enhanced by the administration of the drug at the beginning of the dark phase. Nocturnal mice consumed their food mainly during the dark phase. Our results support the notion that morning administration of EMPA may be effective in suppressing the development of peripheral neuropathy in diabetic patients. SIGNIFICANCE STATEMENT: Empagliflozin, a sodium-glucose cotransporter-2 inhibitor suppressed the development of neuropathic pain hypersensitivity in streptozotocin-induced diabetic model mice in a dosing time-dependent manner.

DOI： 10.1124/jpet.123.001856

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DOI： 10.1016/j.jbc.2021.100601