State Key Laboratory of Common Mechanism Research for Major Diseases & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005, Beijing, China.
Department of Obstetrics and Gynecology, Peking University People's Hospital, 100044, Beijing, China.
Br J Cancer. 2023 Sep;129(4):601-611. doi: 10.1038/s41416-023-02347-2. Epub 2023 Jul 4.
The effectiveness of conservative treatment of endometrial carcinoma (EC) with oral progesterone therapy, such as medroxyprogesterone acetate (MPA), can be blunted due to primary or acquired resistance, but the underlying mechanisms remain incompletely defined.
Genome-wide CRISPR screening was performed to identify potential regulators in response to MPA in Ishikawa cells. Crystal violet staining, RT-qPCR, western blotting, ChIP-qPCR and luciferase assays were employed to elucidate the p53-AarF domain-containing kinase 3 (ADCK3) regulatory axis and its roles in sensitizing EC cells to MPA treatment.
ADCK3 is identified as a previously unrecognized regulator in response to MPA in EC cells. Loss of ADCK3 in EC cells markedly alleviated MPA-induced cell death. Mechanistically, loss of ADCK3 primarily suppresses MPA-mediated ferroptosis by abrogating arachidonate 15-lipoxygenase (ALOX15) transcriptional activation. Moreover, we validated ADCK3 as a direct downstream target of the tumor suppressor p53 in EC cells. By stimulating the p53-ADCK3 axis, the small-molecule compound Nutlin3A synergized with MPA to efficiently inhibit EC cell growth.
Our findings reveal ADCK3 as a key regulator of EC cells in response to MPA and shed light on a potential strategy for conservative EC treatment by activating the p53-ADCK3 axis to sensitize MPA-mediated cell death.
子宫内膜癌（EC）的保守治疗（如醋酸甲羟孕酮）的有效性可能因原发性或获得性耐药而减弱，但潜在机制仍不完全明确。
对 Ishikawa 细胞中 MPA 反应的全基因组 CRISPR 筛选，以鉴定潜在的调节剂。采用结晶紫染色、RT-qPCR、western blot、ChIP-qPCR 和荧光素酶测定法阐明 p53-AarF 结构域激酶 3（ADCK3）调控轴及其在增强 EC 细胞对 MPA 治疗敏感性中的作用。
ADCK3 是 EC 细胞对 MPA 反应中一个以前未被识别的调节剂。EC 细胞中 ADCK3 的缺失显著减轻了 MPA 诱导的细胞死亡。从机制上讲，ADCK3 的缺失主要通过废除花生四烯酸 15-脂氧合酶（ALOX15）转录激活来抑制 MPA 介导的铁死亡。此外，我们在 EC 细胞中验证了 ADCK3 是肿瘤抑制因子 p53 的直接下游靶标。通过刺激 p53-ADCK3 轴，小分子化合物 Nutlin3A 与 MPA 协同作用，有效地抑制 EC 细胞生长。
我们的研究结果揭示了 ADCK3 是 EC 细胞对 MPA 反应的关键调节剂，并为通过激活 p53-ADCK3 轴来增强 MPA 介导的细胞死亡，为保守性 EC 治疗提供了一种潜在的策略。
