Akira Suekane

N-myc downstream-regulated gene 2 (NDRG2), which is a tumour suppressor, is frequently lost in many types of tumours, including adult T-cell leukaemia/lymphoma (ATL). The downregulation of NDRG2 expression is involved in tumour progression through the aberrant phosphorylation of several important signalling molecules. We observed that the downregulation of NDRG2 induced the translocation of protein arginine methyltransferase 5 (PRMT5) from the nucleus to the cytoplasm via the increased phosphorylation of PRMT5 at Serine 335. In NDRG2^low ATL, cytoplasmic PRMT5 enhanced HSP90A chaperone activity via arginine methylation, leading to tumour progression and the maintenance of oncogenic client proteins. Therefore, we examined whether the inhibition of PRMT5 activity is a drug target in NDRG2^low tumours. The knockdown of PRMT5 and binding partner methylsome protein 50 (MEP50) expression significantly demonstrated the suppression of cell proliferation via the degradation of AKT and NEMO in NDRG2^low ATL cells, whereas NDRG2-expressing cells did not impair the stability of client proteins. We suggest that the relationship between PRMT5/MEP50 and the downregulation of NDRG2 may exhibit a novel vulnerability and a therapeutic target. Treatment with the PRMT5-specific inhibitors CMP5 and HLCL61 was more sensitive in NDRG2^low cancer cells than in NDRG2-expressing cells via the inhibition of HSP90 arginine methylation, along with the degradation of client proteins. Thus, interference with PRMT5 activity has become a feasible and effective strategy for promoting cancer vulnerability in NDRG2^low ATL.

Unusual clinical course Metolachlor is a chloroacetamide herbicide that is extensively used worldwide. Ingestion of metolachlor causes acute toxicity via the generation of methemoglobin. Elevated levels of methemoglobin inhibit the transport of oxygen to tissue, causing hypoxia and lactic acidosis. A common treatment approach has been to reduce met-hemoglobin by administration of methylene blue. Herein, we present a case of metolachlor poisoning causing lactic acidosis that was treatable by thiamine administration, in which the methemoglobin level was not elevated. A 61-year-old man was admitted to the emergency room with seizures and impaired consciousness after the ingestion of metolachlor (250 mL, 83%) with the intent to commit suicide. The patient’s methemoglobin and lactate levels on admission were 0.9% and 11.8 mmol/L, respectively. After admission, the levels of lactate decreased gradually; however, they increased 13 h after admission. There was no evidence of heavy alcohol consumption, hyponutrition, or chronic thiamine deficiency. We initially administered a thiamine bolus (100 mg), which immediately improved his consciousness, followed by continuous administration of the same substance (1500 mg/day). The patient’s consciousness improved, and was discharged from the intensive care unit on day 4. Metolachlor can cause metabolic dysfunction and lactic acidosis without an increase in methemoglobin. Moreover, thiamine administration may be beneficial for patients with metolachlor intoxication exhibiting symptoms of elevated lactate levels, impaired consciousness, and lack of elevated methemoglobin levels.