The isomerase PIN1 controls numerous cancer-driving pathways and is a unique drug target

• Published in: Nature reviews. Cancer Vol. 16; no. 7; pp. 463 - 478
• Main Authors: Zhou, Xiao Zhen, Lu, Kun Ping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2016; Nature Publishing Group
• Subjects: 631/337/458/1733; 631/67/1059/602; 631/67/1244; 631/67/395; 631/80/86/2368; Animals; Biomedicine; Cancer Research; Carcinogenesis; Cellular control mechanisms; Genetic aspects; Health aspects; Humans; Innovations; Isomerases; Isomerism; Mice; Molecular targeted therapy; Neoplasms - drug therapy; Neoplasms - enzymology; NIMA-Interacting Peptidylprolyl Isomerase - drug effects; NIMA-Interacting Peptidylprolyl Isomerase - physiology; Properties; review-article
• ISSN: 1474-175X; 1474-1768
• DOI: 10.1038/nrc.2016.49

Key Points In contrast to all other known prolyl isomerases, PIN1 has the unique property of binding to and catalysing the conversion of specific proline-directed serine/threonine phosphorylation motifs between the two distinct cis and trans conformations of proline. Such PIN1-catalysed prolyl isomerization functions as a molecular timer that modulates many targets at various steps of a given cellular process to synchronously control the amplitude and duration of a given cellular response or process. PIN1 is tightly regulated under physiological conditions, but is commonly overexpressed and/or overactivated in most human cancers, with its levels being correlated with clinical outcome in many cancers. By contrast, PIN1 polymorphisms that lower PIN1 expression are associated with reduced risk for multiple cancers. Pin1 -null mice, which develop normally, are highly resistant to tumorigenesis even after overexpression of oncogenes or ablation of tumour suppressors. Conversely, PIN1 overexpression disrupts cell cycle coordination and leads to chromosome instability and tumorigenesis. Abnormal PIN1 activation disrupts the balance in cancer to activate at least 40 oncogenes and inactivate at least 20 tumour suppressors, many of which have a known role in cancer stem cells (CSCs). PIN1 inhibitors have the promising and desirable property of restoring the balance in cancer by simultaneously blocking many cancer-driving pathways in cancer cells and CSCs for treating aggressive and drug-resistant cancers. PIN1 is a major target of the drug all- trans retinoic acid (ATRA) in acute promyelocytic leukaemia. The recent development of cis and trans conformation-specific antibodies provides direct evidence for conformation-specific function and regulation by PIN1, and should facilitate the discovery of novel disease mechanisms and potential new therapies for PIN1-related diseases. Further development of conformation-specific antibodies against oncogenes and tumour suppressors that are PIN1 substrates would provide powerful tools for studying cancer signalling and may lead to new cancer diagnostics and/or therapeutics. This Review discusses PIN1-catalysed prolyl isomerization as a common signalling mechanism to regulate the balance of oncogenes and tumour suppressors. PIN1 inhibitors may be able to restore the balance in cancer cells and cancer stem cells to treat aggressive and drug-resistant tumours. Targeted drugs have changed cancer treatment but are often ineffective in the long term against solid tumours, largely because of the activation of heterogeneous oncogenic pathways. A central common signalling mechanism in many of these pathways is proline-directed phosphorylation, which is regulated by many kinases and phosphatases. The structure and function of these phosphorylated proteins are further controlled by a single proline isomerase: PIN1. PIN1 is overactivated in cancers and it promotes cancer and cancer stem cells by disrupting the balance of oncogenes and tumour suppressors. This Review discusses the roles of PIN1 in cancer and the potential of PIN1 inhibitors to restore this balance.