Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China.
Department of Pharmacology, The School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, Fujian 350122, China.
Pharmacol Res. 2022 Oct;184:106456. doi: 10.1016/j.phrs.2022.106456. Epub 2022 Sep 16.
The development of tumor therapeutic resistance is one of the important reasons for the failure of antitumor therapy. Starting with multiple targets and multiple signaling pathways is helpful in understanding the mechanism of tumor resistance. The overexpression of prolyl isomerase Pin1 is highly correlated with the malignancy of cancer, since Pin1 controls many oncogenes and tumor suppressors, as well as a variety of cancer-driving signaling pathways. Strikingly, numerous studies have shown that Pin1 is directly involved in therapeutic resistance. In this review, we mainly summarize the functions and mechanisms of Pin1 in therapeutic resistance of multifarious cancers, such as breast, liver, and pancreatic carcinomas. Furtherly, from the perspective of Pin1-driven cancer signaling pathways including Raf/MEK/ERK, PI3K/Akt, Wnt/β-catenin, NF-κB, as well as Pin1 inhibitors containing juglone, epigallocatechin-3-gallate (EGCG), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), it is better to demonstrate the important potential role and mechanism of Pin1 in resistance and sensitization to cancer therapies. It will provide new therapeutic approaches for clinical reversal and prevention of tumor resistance by employing synergistic administration of Pin1 inhibitors and chemotherapeutics, implementing combination therapy of Pin1-related cancer signaling pathway inhibitors and Pin1 inhibitors, and exploiting novel Pin1-specific inhibitors.
肿瘤治疗抵抗的发展是抗肿瘤治疗失败的重要原因之一。从多个靶点和多个信号通路入手，有助于了解肿瘤抵抗的机制。脯氨酰异构酶 Pin1 的过表达与癌症的恶性程度高度相关，因为 Pin1 控制着许多癌基因和肿瘤抑制基因，以及多种致癌信号通路。引人注目的是，大量研究表明 Pin1 直接参与了治疗抵抗。在这篇综述中，我们主要总结了 Pin1 在多种癌症（如乳腺癌、肝癌和胰腺癌）治疗抵抗中的功能和机制。此外，从 Pin1 驱动的癌症信号通路（包括 Raf/MEK/ERK、PI3K/Akt、Wnt/β-catenin、NF-κB）的角度，以及包含胡桃醌、表没食子儿茶素没食子酸酯（EGCG）、全反式维甲酸（ATRA）和三氧化二砷（ATO）在内的 Pin1 抑制剂，更好地展示了 Pin1 在癌症治疗抵抗和敏感化中的重要潜在作用和机制。通过协同应用 Pin1 抑制剂和化疗药物、实施 Pin1 相关癌症信号通路抑制剂和 Pin1 抑制剂的联合治疗、以及开发新型 Pin1 特异性抑制剂，为临床逆转和预防肿瘤抵抗提供了新的治疗方法。
