The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
Cell Rep. 2017 Aug 15;20(7):1692-1704. doi: 10.1016/j.celrep.2017.07.055.
Ferroptosis is a form of regulated cell death that may facilitate the selective elimination of tumor cells. The tumor suppressor p53 (TP53) has been demonstrated to promote ferroptosis via a transcription-dependent mechanism. Here, we show that TP53 limits erastin-induced ferroptosis by blocking dipeptidyl-peptidase-4 (DPP4) activity in a transcription-independent manner. Loss of TP53 prevents nuclear accumulation of DPP4 and thus facilitates plasma-membrane-associated DPP4-dependent lipid peroxidation, which finally results in ferroptosis. These findings reveal a direct molecular link between TP53 and DPP4 in the control of lipid metabolism and may provide a precision medicine strategy for the treatment of colorectal cancer by induction of ferroptosis.
铁死亡是一种受调控的细胞死亡形式，可能有助于选择性地消除肿瘤细胞。肿瘤抑制因子 p53（TP53）已被证明通过依赖转录的机制促进铁死亡。在这里，我们表明 TP53 通过非转录依赖的方式阻断二肽基肽酶 4（DPP4）的活性来限制依马替尼诱导的铁死亡。TP53 的缺失阻止了 DPP4 的核积累，从而促进了与质膜相关的 DPP4 依赖性脂质过氧化，最终导致铁死亡。这些发现揭示了 TP53 和 DPP4 在控制脂质代谢中的直接分子联系，并可能为通过诱导铁死亡治疗结直肠癌提供一种精准医学策略。
