Department of Life Science and Research Institute for Natural Sciences, College of Natural Sciences, Hanyang University, Seoul, 04763, South Korea.
Department of Pathology, Hanyang University College of Medicine, Seoul, 04763, South Korea.
Adv Sci (Weinh). 2023 Nov;10(33):e2305096. doi: 10.1002/advs.202305096. Epub 2023 Oct 16.
Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof-of-principle evidence is presented that a cell-penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene-addicted cancer cells through transcription activity-independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2-p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome-wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C-resistant cancers. This study enhances the understanding of ACP52C-induced cancer-specific apoptosis induction and supports the use of ACP52C in anticancer drug development.
尽管在精准肿瘤学方面取得了进展，但癌症仍然是一个全球性的公共卫生问题。在本报告中，提出了一个原理验证的证据，即一种可穿透细胞的肽（ACP52C）通过非转录活性依赖的机制，分离转录因子 CP2c 复合物并诱导大多数 CP2c 癌基因成瘾性癌细胞凋亡。从复合物中解离的 CP2cs 直接与 YY1 相互作用并使其降解，通过 MDM2-p53 途径导致凋亡。释放的 CP2cs 还抑制 TDP2，导致内在的全基因组 DNA 链断裂和随后的灾难性 DNA 损伤反应。这两种机制独立于癌症驱动突变，但受到高 MDM2 p60 表达的阻碍。然而，CP52C 介导的对 MDM2 p60 的耐药性可以通过 CASP2 抑制来敏感化。此外，单独与脂肪酸共轭的 ACP52C 衍生物或与 CASP2 抑制肽共轭的 ACP52C 衍生物显示出改善的药代动力学和降低的癌症负担，即使在 ACP52C 耐药性的癌症中也是如此。这项研究增强了对 ACP52C 诱导的癌症特异性凋亡诱导的理解，并支持将 ACP52C 用于抗癌药物的开发。
