College of Preventive Medicine, Army Medical University, Chongqing 400038, China.
State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, Institute of Combined Injury, Chongqing 400038, China.
Nutrients. 2022 Aug 18;14(16):3395. doi: 10.3390/nu14163395.
Myelosuppression is a common and intractable side effect of cancer therapies including radiotherapy and chemotherapy, while the underlying mechanism remains incompletely understood. Here, using a mouse model of radiotherapy-induced myelosuppression, we show that inorganic phosphate (Pi) metabolism is acutely inhibited in hematopoietic stem cells (HSCs) during irradiation-induced myelosuppression, and closely correlated with the severity and prognosis of myelosuppression. Mechanistically, the acute Pi metabolic inhibition in HSCs results from extrinsic Pi loss in the bone marrow niche and the intrinsic transcriptional suppression of soluble carrier family 20 member 1 (SLC20A1)-mediated Pi uptake by p53. Meanwhile, Pi metabolic inhibition blunts irradiation-induced Akt hyperactivation in HSCs, thereby weakening its ability to counteract p53-mediated Pi metabolic inhibition and the apoptosis of HSCs and consequently contributing to myelosuppression progression. Conversely, the modulation of the Pi metabolism in HSCs via a high Pi diet or renal Klotho deficiency protects against irradiation-induced myelosuppression. These findings reveal that Pi metabolism and HSC survival are causally linked by the Akt/p53-SLC20A1 axis during myelosuppression and provide valuable insights into the pathogenesis and management of myelosuppression.
骨髓抑制是放疗和化疗等癌症治疗的常见且棘手的副作用，但其潜在机制仍不完全清楚。在这里，我们使用放射诱导骨髓抑制的小鼠模型，表明在照射诱导的骨髓抑制期间，造血干细胞 (HSC) 中的无机磷酸盐 (Pi) 代谢被急性抑制，并且与骨髓抑制的严重程度和预后密切相关。从机制上讲，HSCs 中的急性 Pi 代谢抑制是由于骨髓龛中外源性 Pi 丢失以及 p53 介导的 Pi 摄取的溶质载体家族 20 成员 1 (SLC20A1) 内在转录抑制所致。同时，Pi 代谢抑制削弱了照射诱导的 HSCs 中 Akt 的过度激活，从而削弱了其抵消 p53 介导的 Pi 代谢抑制和 HSCs 凋亡的能力，从而导致骨髓抑制进展。相反，通过高 Pi 饮食或肾脏 Klotho 缺乏调节 HSCs 中的 Pi 代谢可预防照射诱导的骨髓抑制。这些发现表明，在骨髓抑制期间，Akt/p53-SLC20A1 轴将 Pi 代谢和 HSC 存活联系起来，并为骨髓抑制的发病机制和治疗提供了有价值的见解。
