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Review
. 2024 Apr 30:12:1343938.
doi: 10.3389/fcell.2024.1343938. eCollection 2024.

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

Robert Stewart #  1 , Shaunik Sharma #  1 , Timothy Wu  1 , Sho Okuda  1 , George Xie  1 , Xiao Zhen Zhou  1   2   3   4 , Brian Shilton  1 , Kun Ping Lu  1   2   4   5
Affiliations
Review

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

Robert Stewart et al. Front Cell Dev Biol. .

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.

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Conflict of interest statement

XXZ and KPL are inventors of several patents and patent application related to Pin1, as well as the scientific founders and former scientific advisors of and own equity in Pinteon. Their interests were reviewed and are managed by Western University in accordance with its conflict-of-interest policy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Pin1 promotes the proteasomal degradation of tumor suppressor protein FBXW7 and stabilizes oncogenes to promote oncogenesis. (A) PDSTK-mediated phosphorylation on the Thr205-Pro206 motif on tumor suppressor protein FBXW7 facilitates interactions with Pin1, which inhibits FBXW7 dimerization, resulting in self-ubiquitination and subsequent proteasomal degradation. Downstream FBXW7 substrates such as Notch1, Jun, and c-Myc are stabilized, which promote oncogenesis. (B) Pin1 interacts with the oncoprotein Oct4 following its PDSTK-mediated phosphorylation. Pin1 increases Oct4 stability by inhibiting ubiquitination and degradation, resulting in enhanced transcriptional activity. Increased Oct4 inhibits the transcription of tumor suppressors and promotes oncogene transcription; together these effects promote oncogenesis. Abbreviations: FBXW7, F-box and WD repeat domain containing 7; Notch1, neurogenic locus notch homolog protein 1; Jun; c-Myc, c-myelocytomatosis oncogene; Mcl-1, myeloid cell leukemia sequence 1; mTOR, mammalian target of rapamycin; Oct4, octamer-binding transcription factor 4; Sox2, SRY-box 2; PTEN, phosphatase and tensin homolog; RAB37, member Ras oncogene family 37; DKK3, dickkopf-3. The figure was generated using BioRender®.
FIGURE 2
FIGURE 2
Pin1 regulates various oncoproteins and tumor suppressor proteins to sustain a cancer stem cell phenotype. Depiction of a cancer stem cell. Green arrows indicate positive regulation (activation), and red lines represent negative regulation (inhibition). Abbreviations: DAXX, death domain-associated protein; MDM2, mouse double minute homolog; NF-ĸB, nuclear factor kappa-light-chain-enhancer of activated B cells; GLI1 glioma-associated oncogene homolog 1; JAG1, jagged1; AMPK, AMP-activated protein kinase; BRAF, v-raf murine sarcoma viral homolog B1; SOX2, SRY-box 2; mTOR, mammalian target of rapamycin; STAT3, signal transducer and activator of transcription 3; Oct-4, octamer-binding transcription factor 4; PKB, protein kinase B; PTEN, phosphatase and tensin homolog; ZEB1, zinc finger E-box binding homeobox 1, Wnt5a, wingless/integrated-5a; RARα, retinoic acid receptor α; FOXM1, forkhead box protein M1; c-myc, c-myelocytomatosis oncogene; RAB2A, member Ras oncogene family; FBXW7, F-box and WD repeat domain containing 7; Notch1, neurogenic locus notch homolog protein 1. The figure was generated using BioRender®.
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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.