Wang Lu, Fu Bo, Hou Da-Yong, Lv Yu-Lin, Yang Guang, Li Cong, Shen Jia-Chen, Kong Bin, Zheng Li-Bo, Qiu Yu, Wang Hong-Lei, Liu Chen, Zhang Jian-Ji, Bai Shi-Yu, Li Li-Li, Wang Hao, Xu Wan-Hai
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China; Department of Urology, The Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, No. 37 Yi-Yuan Street, Nangang District, Harbin, Heilongjiang Province, 150081, China.
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China; Department of Urology, The Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, No. 37 Yi-Yuan Street, Nangang District, Harbin, Heilongjiang Province, 150081, China; CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST) No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, China.
Biomaterials. 2023 May;296:122060. doi: 10.1016/j.biomaterials.2023.122060. Epub 2023 Mar 1.
Stronger intrinsic Warburg effect and resistance to chemotherapy are the responses to high mortality of renal cell carcinoma (RCC). Pyruvate kinase M2 (PKM2) plays an important role in this process. Promoting PKM2 conversion from dimer to tetramer is a critical strategy to inhibit Warburg effect and reverse chemotherapy resistance. Herein, a PKM2 allosteric converter (PAC) is constructed based on the "in vivo self-assembly" strategy, which is able to continuously stimulate PKM2 tetramerization. The PAC contains three motifs, a serine site that is protected by enzyme cleavable β-N-acetylglucosamine, a self-assembly peptide and a AIE motif. Once PAC nanoparticles reach tumor site via the EPR effect, the protective and hydrophilic β-N-acetylglucosamine will be removed by over-expressed O-GlcNAcase (OGA), causing self-assembled peptides to transform into nanofibers with large serine (PKM2 tetramer activator) exposure and long-term retention, which promotes PKM2 tetramerization continuously. Our results show that PAC-induced PKM2 tetramerization inhibits aberrant metabolism mediated by Warburg effect in cytoplasm. In this way, tumor proliferation and metastasis behavior could be effectively inhibited. Meanwhile, PAC induced PKM2 tetramerization impedes the nuclear translocation of PKM2 dimer, which restores the sensitivity of cancer cells to first-line anticancer drugs. Collectively, the innovative PAC effectively promotes PKM2 conversion from dimer to tetramer, and it might provide a novel approach for suppressing RCC and enhancing chemotherapy sensitivity.
更强的内在沃伯格效应和对化疗的抗性是肾细胞癌（RCC）高死亡率的应对机制。丙酮酸激酶M2（PKM2）在此过程中发挥重要作用。促进PKM2从二聚体向四聚体的转变是抑制沃伯格效应和逆转化疗抗性的关键策略。在此，基于“体内自组装”策略构建了一种PKM2变构转换器（PAC），其能够持续刺激PKM2四聚化。PAC包含三个基序，一个由酶可切割的β-N-乙酰葡糖胺保护的丝氨酸位点、一个自组装肽和一个聚集诱导发光（AIE）基序。一旦PAC纳米颗粒通过增强渗透滞留（EPR）效应到达肿瘤部位，过表达的O-连接N-乙酰葡糖胺酶（OGA）会去除保护性和亲水性的β-N-乙酰葡糖胺，导致自组装肽转变为具有大量丝氨酸（PKM2四聚体激活剂）暴露和长期滞留的纳米纤维，从而持续促进PKM2四聚化。我们的结果表明，PAC诱导的PKM2四聚化抑制了细胞质中由沃伯格效应介导的异常代谢。通过这种方式，肿瘤增殖和转移行为可得到有效抑制。同时，PAC诱导的PKM2四聚化阻碍了PKM2二聚体的核转位，从而恢复了癌细胞对一线抗癌药物的敏感性。总体而言，创新性的PAC有效促进了PKM2从二聚体向四聚体的转变，可能为抑制肾细胞癌和增强化疗敏感性提供一种新方法。
