Prolyl isomerase Pin1: a promoter of cancer and a target for therapy

Abstract

Pin1 is the only known peptidyl-prolyl cis–trans isomerase (PPIase) that specifically recognizes and isomerizes the phosphorylated Serine/Threonine-Proline (pSer/Thr-Pro) motif. The Pin1-mediated structural transformation posttranslationally regulates the biofunctions of multiple proteins. Pin1 is involved in many cellular processes, the aberrance of which lead to both degenerative and neoplastic diseases. Pin1 is highly expressed in the majority of cancers and its deficiency significantly suppresses cancer progression. According to the ground-breaking summaries by Hanahan D and Weinberg RA, the hallmarks of cancer comprise ten biological capabilities. Multiple researches illuminated that Pin1 contributes to these aberrant behaviors of cancer via promoting various cancer-driving pathways. This review summarized the detailed mechanisms of Pin1 in different cancer capabilities and certain Pin1-targeted small-molecule compounds that exhibit anticancer activities, expecting to facilitate anticancer therapies by targeting Pin1.

Activity-dependent isomerization of Kv4.2 by Pin1 regulates cognitive flexibility

“…Pin1 is a peptidyl-prolyl cistrans isomerase that catalyzes the isomerization of peptidyl-prolyl peptide bonds. Pin1 differs from other isomerases as it is, so far, the only known prolyl isomerase that specifically catalyzes isomerization of certain Ser/Thr-Pro bonds upon their phosphorylation 54 . Isomerization of Ser/Thr-Pro motifs is especially important because kinases and phosphatases specifically recognize the cis or trans conformation of the prolyl peptide bond of their substrates 55 and phosphorylation further slows down the isomerization rate of proline 56 .…”

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Several proteins regulate STAT3 activation through direct interaction with STAT3. Pin1 is highly expressed in a majority of cancers [92,93], and elevation in Pin1 levels by either OSM or IL-6 involves the activation of both STAT3 and NF-κB through direct binding with the pSer/Thr-Pro motifs of STAT3 and p65 in the nucleus that results in promotion of STAT3 transcriptional activation [94,95]. The activation of RAC1 (RAC1-GTP) by TGF-β-induced PKC-ι results in STAT3 activation via RAC1-GTP-mediated triggering of the IL-6/JAK and Rac1-JNK pathways, or via its interaction with STAT3 [96][97][98][99].…”

Sulfopin, a selective covalent inhibitor of Pin1, blocks Myc-driven tumor initiation and growthin vivo

“…Pin1-mediated isomerization was shown to impact substrate stability [5][6][7][8][9] , activity 10,11 , subcellular localization 8 , and binding to interaction partners, including Prolinedirected kinases and phosphatases, which are mostly trans-specific [12][13][14] . Thus, Pin1 represents a unified signaling hub that is exploited by cancer to activate oncogenes and inactivate tumor suppressors 15,16 .…”

“…While elevated Pin1 expression correlates with poor clinical prognosis 18,19 , polymorphisms that lower Pin1 expression are associated with reduced cancer risk 20 . Pin1 sustains proliferative signaling in cancer cells by upregulating over 50 oncogenes or growth-promoting factors 15,16 , including NF-κB 9 , Notch1 21 and c-Myc 22 , while suppressing over 20 tumor suppressors or growth-inhibiting factors, such as FOXOs 23 , Bcl2 24 and RARα 25 . Furthermore, Pin1-null mice are resistant to tumorigenesis induced by mutant p53 26 , activated HER2/RAS 27 , or constitutively expressed c-Myc 28 .…”