The role of the master cancer regulator Pin1 in the development and treatment of cancer

Robert Stewart; Shaunik Sharma; Timothy Wu; Sho Okuda; George Xie; Xiao Zhen Zhou; Brian Shilton; Kun Ping Lu

doi:10.3389/fcell.2024.1343938

The role of the master cancer regulator Pin1 in the development and treatment of cancer

Front Cell Dev Biol. 2024 Apr 30:12:1343938. doi: 10.3389/fcell.2024.1343938. eCollection 2024.

Authors

Robert Stewart^#¹, Shaunik Sharma^#¹, Timothy Wu¹, Sho Okuda¹, George Xie¹, Xiao Zhen Zhou^{1

2

3

4}, Brian Shilton¹, Kun Ping Lu^{1

2

4

5}

Affiliations

¹ Department of Biochemistry, Western University, London, ON, Canada.
² Robarts Research Institute, Western University, London, ON, Canada.
³ Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
⁴ Lawson Health Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁵ Department of Oncology, Western University, London, ON, Canada.

^# Contributed equally.

Abstract

This review examines the complex role of Pin1 in the development and treatment of cancer. Pin1 is the only peptidyl-prolyl isomerase (PPIase) that can recognize and isomerize phosphorylated Ser/Thr-Pro peptide bonds. Pin1 catalyzes a structural change in phosphorylated Ser/Thr-Pro motifs that can modulate protein function and thereby impact cell cycle regulation and tumorigenesis. The molecular mechanisms by which Pin1 contributes to oncogenesis are reviewed, including Pin1 overexpression and its correlation with poor cancer prognosis, and the contribution of Pin1 to aggressive tumor phenotypes involved in therapeutic resistance is discussed, with an emphasis on cancer stem cells, the epithelial-to-mesenchymal transition (EMT), and immunosuppression. The therapeutic potential of Pin1 inhibition in cancer is discussed, along with the promise and the difficulties in identifying potent, drug-like, small-molecule Pin1 inhibitors. The available evidence supports the efficacy of targeting Pin1 as a novel cancer therapeutic by analyzing the role of Pin1 in a complex network of cancer-driving pathways and illustrating the potential of synergistic drug combinations with Pin1 inhibitors for treating aggressive and drug-resistant tumors.

Keywords: Pin1 inhibition; cancer stem cells; cancer therapy; combination therapy; epithelial–mesenchymal transition; immunosuppression; oncogenesis; peptidyl–prolyl isomerase.

Publication types

Review

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was funded by the Natural Sciences and Research Council of Canada to BHS Canadian Institutes of Health Research to KPL and the Canada Foundation for Innovation (CFI) grants, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research to KPL and XZZ.